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Increased Sympathetic Drive, Elevated Heart Rate,and the Cardiovascular Continuum
  JOHTN
MECHANISMS
Increased Sympathetic Drive, Elevated Heart Rate,
and the Cardiovascular Continuum
Brent M Egan
Vice-President
Care Coordination Institute, Greenville Health SystemGreenville, South Carolina, USA; Department of MedicineUniversity of South Carolina, School of Medicine, ColumbiaSouth Carolina, USA
Corresponding Author: Brent M Egan, Vice-President, CareCoordination Institute, Greenville Health System, GreenvilleSouth Carolina, USA; Department of Medicine, University ofSouth Carolina, School of Medicine, Columbia, South CarolinaUSA
Phone: +8645222261
e-mail: began@ccihealth.org
 
ABSTRACT
The cardiovascular continuum has been recognized for thepast three decades in which antecedent risk factors, includinghypertension and obesity, contribute to structural and functionalcardiac and vascular changes. These risk factors andpathophysiological changes lead to left ventricular hypertrophy,myocardial infarction, cardiac dysfunction, heart failure, anddeath. Sudden death occurs more often among individuals withleft ventricular hypertrophy, myocardial infarction, and heartfailure. Several lines of evidence establish links between thesympathetic nervous system (SNS), heart rate, and cardiovascularrisk factors, such as hypertension, inflammation, insulinresistance, and diabetes. These antecedent factors, withongoing contributions from increased sympathetic drive andfaster heart rates, often progress to asymptomatic functionaland structural cardiovascular disease and subsequently to clinicalcardiovascular disease and death, including sudden death.Increased sympathetic drive and faster heart rates can reflectfamilial and presumably genetic factors, various acute andchronic stressors, and obesity, especially abdominal-visceralobesity, which alter sympathovagal balance. Interventions,including lifestyle changes and pharmacotherapy that reduceheart rate and sympathetic drive, can interrupt the cardiovascularcontinuum at several points in this progressively deleteriouspathway. Given the global obesity epidemic and the stressesof contemporary life, which can include crime, noise, and lessstable families, it is important for clinicians to understand therole of increased sympathetic drive and faster heart rates inthe continuum of cardiovascular risk, clinical cardiovasculardisease, and death. Clinicians should be prepared to offer theirpatients lifestyle guidance and pharmacotherapy to interruptthis continuum and enhance cardiovascular health.
Keywords: Cardiovascular disease, Nonadherence, Officeresistance, Pseudoresistant hypertension, Spironolactone,Treatment-resistant hypertension.
How to cite this article: Egan BM. Increased SympatheticDrive, Elevated Heart Rate, and the Cardiovascular Continuum.Hypertens J 2017;3(3):105-112.
Source of support: Nil
Conflict of interest: None
 
 

 
OVERVIEW

This review begins with the relationship betweensympathetic drive and heart rate at each step along thecontinuum of cardiovascular disease, which has beenadapted from the work of Drs Vasan and Levy1 (Fig. 1).As shown, heightened sympathetic drive and faster heartrates are linked with endothelial dysfunction, markers ofsystemic inflammation, incident hypertension and diabetes,left ventricular hypertrophy, vascular remodeling,myocardial infarction, systolic dysfunction, heart failure,and death. Left ventricular hypertrophy, myocardialinfarction, and heart failure are also associated with anincreased risk of sudden death. Increased sympatheticdrive and faster heart rate contribute to sudden death.

Faster heart rates beginning in the upper seventies(beats per minute), which often receive little to noclinical attention, are associated with increased riskfor hypertension, diabetes, cardiovascular events, andsudden death. Moreover, increased sympathetic driveand faster heart rates participate in the systolic dysfunctionthat often follows a myocardial infarction includingprogression to heart failure. Among patients with heartfailure, increased sympathetic drive and faster heart ratesare linked with morality and sudden death. While notshown, ß-adrenoceptor blocking agents can interruptthis continuum at several points in the progression withstronger evidence for secondary than primary preventionof cardiovascular disease.

In the beginning, increased sympathetic drive andfaster heart rates contribute to cardiovascular risk factorsincluding hypertension and diabetes. The genesis orstarting point for elucidating an important role forincreased sympathetic drive and faster heart rates to thecardiovascular continuum is perhaps the most importantas one could posit that the later changes simply reflectthe response to the underlying pathophysiologicalchanges. Consequently, this section on the relationshipof increased sympathetic drive and faster heart rates inthe initial stages of the cardiovascular continuum areprovided in more details than the middle and late phasesof the continuum which follow.

The antecedents of cardiovascular disease typicallybegin with few if any classical clinical symptoms. Theseantecedents include endothelial dysfunction, a relativeresting tachycardia, modest nonhypertensive elevations of blood pressure, hyperinsulinemia, insulin resistance,a complex dyslipidemia, and markers of systemic inflammation(Fig. 1). The complex dyslipidemia associated withinsulin resistance is typically characterized by modestelevations of triglycerides and reductions of high-densitylipoprotein (HDL) cholesterol, and denser low-densitylipoprotein (LDL) cholesterol with heightened sensitivityto oxidative changes, which renders it more atherogenic.2Pathologic changes in the lipoprotein profile can occurwithout clinically elevated total or LDL-cholesterol, andrequires heightened clinical awareness for detection. Leftunchecked, these antecedents can progress to clinicalhypertension and diabetes.

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Increased Sympathetic Drive, Elevated Heart Rate,and the Cardiovascular Continuum
Fig. 1: The cardiovascular continuum viewed from a neurogenic perspective.1 Increased SNS activity and faster HR are associatedwith endothelial dysfunction, inflammation, incident hypertension and diabetes, LVH, vascular remodeling, and MI; LVH and MI arelinked with sudden death. Increased SNS activity and faster HR participate in the systolic dysfunction that often follows an MI includingprogression to HF; HF, in turn, substantially increases mortality including sudden death, which are associated with increased SNSdrive and faster HR. While not shown, ß-blockers can interrupt this continuum with stronger evidence for secondary than primaryprevention of cardiovascular disease. LVH: Left ventricular hypertrophy; MI: Myocardial infarction

A substantial body of literature links heightenedsympathetic drive and a relative tachycardia to the aforementionedantecedents of hypertension and dysglycemia,which include endothelial dysfunction, systemic inflammation,and insulin resistance.3-7 Graph 1, adapted fromprior publications, displays the link between a relativeresting tachycardia and subsequent development of clinicalhypertension and diabetes.3,4

Progression from Sympathetic Overdrive and
Faster Heart Rates to Hypertension


Harburg et al8 reported that male college students withsustained elevations of blood pressure at screening andhome described themselves as motivated to obtain socialcontacts, but in a "sensitive" and "anxious" manner. Youngmen who had an elevated screening and subsequent office blood pressure yielded more frequently in an argumentand subsequently change their private opinions toagree with partners who had lower blood pressures. Asubsequent study found that among undergraduate menwith elevated screening blood pressures, the subset withelevated blood pressure values at home reported greaterintensity of anger and suppressed their anger to a greaterextent than those with normal home blood pressure.9
 
Anger, Increased Sympathetic and Reduced
Parasympathetic Tone


Marci et al10 studied emotional recall and sympatheticand parasympathetic activity. Of emotions studied,only anger was linked with increased sympathetic anddecreased parasympathetic activity.

Role of Sympathetic Activation and Parasympathetic
Inhibition in the Hyperkinetic Hemodynamic Profile
of Borderline Hypertension


Hyperkinetic borderline hypertensives had higher valuesthan healthy normal controls for cardiac index and heartrate (Graph 1). ß-adrenoceptor blockade led to a larger fallof cardiac index and heart rate among individuals withhyperkinetic borderline hypertension than controls, yetvalues remained higher in the hyperkinetic group. Withatropine to block cardiac vagal tone, cardiac output andheart rate increased less in subjects with hyperkineticborderline hypertension than in normal controls andwere no longer different from normal controls.11 These data suggest that increased sympathetic and reducedparasympathetic tone contribute to hyperkinetic prehypertension.
 
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Increased Sympathetic Drive, Elevated Heart Rate, and the Cardiovascular Continuum

Increased Sympathetic Drive, Elevated Heart Rate,and the Cardiovascular Continuum
Graph 1: Sympathovagal imbalance plays a major role in the cardiac changes characteristic ofhyperkinetic prehypertension.11 Baseline heart rate and cardiac index are higher in hyperkineticprehypertensives than age- and sex-matched normal controls. After ß-adrenoceptor blockade withpropranolol, heart rate and cardiac index decline more in the hyperkinetic prehypertensive thannormal group, yet values remain higher in the former. With addition of the muscarinic receptorantagonist atropine to eliminate cardiac vagal tone, heart rate and cardiac index increase less inthe hyperkinetic than in the control group. At that point, group difference in heart rate and cardiacindex was no longer significant

Transition from Hyperkinetic Borderline
Hypertension to Normokinetic Borderline
and Established Essential Hypertension


It is important to note that studies employing musclesympathetic nerve activity and norepinephrine turnoverdocumented sympathetic overactivity in a large proportion of adults with essential hypertension includingthose who are obese.12-14 Faster heart rates, evenwithin the range of 60 to 100 that are considered normal,are linked with incident hypertension (Graph 2).3Many hyperkinetic subjects appear to develop classicalestablished hypertension over time,15 yet thehyperkinetic state is much less common in adults withhypertension. Thus, a transition almost certainly occursfrom the hyperkinetic borderline hypertension to normokinetic,high-resistance hypertension.15
 

Increased Sympathetic Drive, Elevated Heart Rate,and the Cardiovascular Continuum
Graphs 2A and B: (A)Transient tachycardia and transient hypertension increase risk for future (upper),3 while relative restingtachycardia raises risk for diabetes (lower).48 Upper panel: The relationship between transient tachycardia [(tTachy) ≥100 beats/min],transient hypertension [(tHTN) ≥150/≥90 mm Hg] on risk of future hypertension is shown. Both transient tachycardia and transienthypertension approximately double the risk for future hypertension, whereas the combination of both trebles risk. Adapted from data inreference Levy et al.3 (B) Lower panel: Resting heart rate and the adjusted odds ratio for future diagnosis of diabetes mellitus (Dx DM)and death (DM Death) are shown. Heart rate and risk of diabetes were similar in younger (< 50 years) and older (≥50 years) patientsat baseline, whereas the risk of death was observed only in those < 50 years at baseline (odds ratio death shown only for < 50 yearsgroup). Adapted from data in Carnethon et al4

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Julius et al16 conducted studies supporting a transitionfrom neurogenic hyperkinetic to neurogenic normokineticprehypertension and established hypertension. Heart ratewas elevated less in subjects with prehypertension andnormal cardiac output than in hyperkinetic prehypertensives.After cardiac autonomic blockade with propranololand atropine, cardiac output in "normokinetic" prehypertensivegroup was lower than in normal controls. Heartrate responses to isoproterenol were less in the normokineticprehypertensives than normal controls and likelyreflect ß-adrenoceptor downregulation in response to persistentelevations of sympathetic drive. Following cardiacautonomic blockade, the mild blood pressure elevationin the normokinetic prehypertensives was sustained byincreased vascular resistance, a key pathophysiologicalfeature in human essential hypertension.

Esler et al17,18 then showed that the elevated bloodpressure in prehypertensive and hypertensive individualswith high plasma renin activity values wasneurogenic. The effects of heightened sympatheticdrive include high plasma renin activity via activationof ß-adrenoceptors on renin secreting cells of thejuxtaglomerular apparatus. Following total autonomicblockade with propranolol (ß-adrenoceptor antagonist,atropine vagolytic, muscarinic receptor antagonist) andphentolamine (α-adrenoceptor antagonist), blood pressurevalues declined to normal in the high-renin group,while remaining elevated in the low and middle reningroups. Subsequent studies with regional infusions ofphentolamine in the human forearm confirmed the presenceof increased vascular α-adrenergic tone at an earlystage of hypertension and in obese prehypertensives.19,20

Mechanisms underlying the Hemodynamic
Transition from Hyperkinetic Borderline
Hypertension to Normokinetic Hypertension
  • Decreased ß-adrenergic sensitivity, cardiovascularremodeling, increased vascular α-adrenergic tone,and resetting of renal pressure-natriuresis.
  • Cardiac changes. Sustained increases in cardiac sympatheticdrive lead to decreased chronotropic andinotropic and probably to the lusitropic responsesto. ß1-adrenoceptor activation.16,21-23 Julius and Majahalme22proposed that the combination of downregulationof cardiac ß1-adrenergic receptors with decreasedchronotropic and inotropic responses to sympatheticdrive together with decreased cardiac complianceand stroke volume contribute to the normalization ofcardiac output in established hypertension.
  • Vascular changes. Concurrent structural vascular remodelingsecondary to elevated blood pressure and sympatheticdrive support the progressive rise in vascularresistance.24,25 Folkow26 was a pioneer in showing how an increased wall:lumen ratio contributes to hypertensionby raising vascular resistance and nonspecificallyamplifying resistance responses to various vasoconstrictors.Subsequent studies by the Ann Arbor groupin relatively young subjects with Stage 1 hypertensioncompared with demographically and weight-matchednormotensive controls were consistent with vascularremodeling as a nonspecific amplifier of arterialresistance in response to different vasoconstrictors.19,27Vasodilator responses in the forearm to regional phentolaminewere also greater in Stage 1 hypertension thanin controls, indicating greater vascular α-adrenoceptormediatedtone.19

 
Resetting of the Renal Pressure/Natriuresis
Relationship


Guyton and Coleman28 demonstrated that the kidney isthe predominant long-term regulator of arterial bloodpressure.29 Unless the renal pressure natriuresis relationshipis set to a higher level, then hypertension cannot besustained. Similarly, lifestyle and/or pharmacotherapythat produce a sustained reduction in blood pressuremust lower the pressure set point for renal pressure/natriuresis. The increased sympathetic drive can resetthe renal pressure/natriuresis threshold upward byincreasing renin secretion and the subsequent cascade toangiotensin II and aldosterone and by directly activatingα1-adrenoceptors on the renal tubules.30,31 In humans,acute stress induced significant renal sodium retentionthat correlated directly with the rise of heart rate, withthe clear implication that both were neurogenically mediated.32 Moreover, long-term studies in animals documentthat stress can induce a sustained resetting of the renalpressure/natriuresis relationship to higher pressure.33

Sympathetic Activation and the
Cardiometabolic Syndrome


In a community, population-based sample of youngadults, Julius et al34 demonstrated that heart rate, a markerof sympathetic activation, correlated with several cardiometabolicsyndrome features, including insulin, glucose,triglycerides, and HDL-cholesterol in young adults at anearly phase of hypertension.7 The relationship betweenheart rate and hyperinsulinemia was especially strong.The hyperinsulinemia most likely represents a compensatoryresponse to insulin resistance given the inverserelationship with HDL-cholesterol and direct link withhypertriglyceridemia.

Sympathetic Drive in Hypertension and Diabetes

Direct sympathetic nerve recordings in patients withhypertension alone, diabetes alone, and both hypertension and diabetes together. Compared with normal control,hypertension and diabetes are each associated withincreased sympathetic neural activity (Graph 3).35 Thecombination of hypertension and diabetes is linked withgreater sympathetic nerve activity than either of the componentconditions alone. Evidence presented subsequentlysuggests this heightened sympathetic activity contributesto the insulin resistance in patients with diabetes and/orhypertension as well as the heightened risk linked withdiabetes and hypertension alone and the amplified riskwhen both are present.
 
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Increased Sympathetic Drive, Elevated Heart Rate, and the Cardiovascular Continuum

Increased Sympathetic Drive, Elevated Heart Rate,and the Cardiovascular Continuum
Graph 3: Sympathetic nerve activity in hypertension and diabetesalone and combined.36 Muscle sympathetic activity in bursts orimpulses/100 heart beats is shown for normotensive (NT) controls,patients with diabetes (DM) and essential hypertension (EHT) alone,and the combination (EHT + DM). Sympathetic nerve activity isincreased in both DM and EHT compared with NT controls andgreater in EHT + DM than with DM or EHT separately

Skeletal muscle is a key target organ for insulinaction.36 Resistance to insulin-mediated glucose disposal,a dominant feature of the cardiometabolic syndrome, isexacerbated by increased vascular α-adrenergic tone,37,38a key feature in neurogenic hypertension.17,18 Jamersonet al37,38 demonstrated that insulin-mediated glucosedisposal in the human forearm was acutely reducedin response to thigh-cuff inflation. This stimulus poolsblood in the lower extremities, thereby unloading cardiopulmonarymechanoreceptors and inducing reflex neurogenicforearm vasoconstriction. With similar reductionsin forearm blood flow, reflex neurogenic vasoconstrictioninduced more forearm insulin resistance than an intraarterialnorepinephrine infusion. Thus, reflex neurogenicvasoconstriction reduced glucose utilization by mechanismsother than or in addition to reduced blood flow.

Jamerson et al37,38 cited evidence that reflex neurogenicvasoconstriction reduces the number of open capillariesin skeletal muscle. Capillary density in skeletal muscleis a major determinant of insulin-mediated glucosedisposal.39 Their experimental data suggested that neurogenically-mediated vasoconstriction,37,38 observedin high-renin patients with borderline and establishedessential hypertension,17,18 significantly diminishesinsulin-mediated glucose disposal in skeletal muscle.This notion is consistent with studies showing thatselective α1-adrenoceptor antagonists improve insulinmediatedglucose disposal in hypertensive patientsto a greater extent than renin/angiotensin systemblockers.40,41 Subjects in the Tecumseh Blood PressureStudy who had higher hematocrits, which likely reflecta neurogenically mediated reduction in plasma volume,also had greater values for plasma norepinephrine andrenin values than healthy controls.42,43

 
MID-PHASE OF THE CARDIOVASCULAR
CONTINUUM AND THE ROLE OF INCREASED
SYMPATHETIC DRIVE AND FASTER
HEART RATES


Overview

Obesity, hypertension, and diabetes are associated withleft ventricular hypertrophy. These three risk factorstogether with the dyslipidemia, inflammation, andthrombogenic diathesis are associated with atherosclerosisand related clinical events including acute myocardialinfarction and stroke. Left ventricular hypertrophy andacute myocardial infarction, in turn, are associated withsudden death.

Sympathetic Drive, Left Ventricular Hypertrophy
in Hypertension, and Sudden Death


In a study of hypertensive patients, the subset withgreater muscle sympathetic nerve activity had greaterleft ventricular mass than those with lower levels ofmuscle sympathetic nerve activity.44 It is likely thatdifference in sympathetic nerve activity contributed tothe left ventricular hypertrophy as arterial blood pressureswere similar in the two groups. In adults with leftventricular hypertrophy, the incidence of sudden deathincreases from ∼0.25% annually to 1.8% annually as wallthickness increases from 16 to 19 mm to >30 mm.45 Inthe Framingham Heart Study, increased left ventricularmass and left ventricular hypertrophy were associatedwith a significantly increased risk for sudden death.46 Theabsolute risk for sudden death with cardiac hypertrophywas greater in men than women in Framingham.

Heart Rate, Cardiovascular Events, and Mortality

Among men in the Paris Prospective study, the subsetwith resting heart rates of 65 to 70 had roughly a 50%increase in the relative risk of death from myocardialinfarction, cardiovascular disease, and all-causes as well as a doubling in risk of sudden death compared with menwith resting heart rates < 60 beats/minute (Graph 4).47Among men with resting heart rates above 75 beatsmen, death from myocardial infarction, cardiovasculardisease and all-cause were double and sudden death isfour-fold higher than in men with resting heart rates< 60 beats/minute. Similar results were observed amongmen in the Framingham Heart Study with death ratesfrom myocardial infarction, cardiovascular disease, andall-cause substantially higher in the groups with heartrates 75 to 84 and >84 beats/minute than in those withheart rate < 65 beats/minute.48 These studies confirmthat a relative resting tachycardia, which often does notreceive clinical attention, is not benign but associatedwith clinically important excess risk for cardiovascularand all-cause mortality.
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Increased Sympathetic Drive, Elevated Heart Rate,and the Cardiovascular Continuum
Graph 4: Resting heart rate and morality among men in the ParisProspective Study.48 A total of 7,079 men ages 42 to 53 years werefollowed for 23 years in the Paris Prospective Study.48 The relativerisks for total, cardiovascular, and sudden death as well as fatalmyocardial infarction are shown with quintile one as the referencegroup. As indicated, relatively modest elevations of resting heartrates, which are often considered normal, were associated with anincreased relative risk of death, particularly sudden death

Heart Rate and Outcomes in Adults with
Treated Hypertension at High Risk for
Cardiovascular Events


In the Valsartan, Amlodipine Long-term Use Evaluation(VALUE) study, individuals with blood pressure controlledto < 140/< 90 but heart rates in the upper quintile, withresting heart rate of ∼80 beats/minute and higher, had a53% higher incidence of the primary outcome of nonfatalheart disease and stroke and cardiovascular death thanthose with controlled blood pressure and heart rate inthe lower four quintiles.49 Patients with heart rates in theupper quintile and controlled hypertension had a minimalreduction in events compared with those with heart ratesin the upper quintile and uncontrolled hypertension.


 
Heart rate is a relevant predictor of cardiovascularoutcomes in adults who are treated for hypertension.However, the management of heart rate in hypertensivepatients for the primary prevention of cardiovasculardisease remains controversial with a limited evidencebase to guide clinicians.50 In contrast, evidence forß-blockers in secondary prevention for adults with coronaryheart disease or chronic heart failure and reducedejection fraction (HFrEF) is solid.

LATE PHASE OF THE CARDIOVASCULAR
CONTINUUM: HFrEF AND DEATH


Faster heart rates and increased sympathetic drive measuredby plasma norepinephrine and muscle sympatheticnerve activity are associated with poor outcomes inpatients in the latter phase of the cardiovascular continuum.The poor outcomes include the developmentof HFrEF and related hospitalization and death.51,52 Theassociation of faster heart rates with adverse outcomesis clearly evident among heart failure with preservedEF patients with sinus rhythm but less apparent inthose with atrial fibrillation.53 Moreover, the benefits ofß-blockers at this late stage for reducing hospital admissionsand death have been linked to heart rate reduction.53,54 Ivabradine, which lowers heart rate througheffects on the funny channels in sinoatrial pacemakercells, is also proven to reduce hospital admissions inHFrEF patients.55

SUMMARY

We have examined evidence that increased sympatheticdrive and/or faster heart rates contribute to the pathogenesisand complications of the cardiovascular continuum.There is substantial evidence for the SNS and faster heartrates as primary factors in the early phase of the continuum.Behavioral factors and environmental stressorsincluding access to excess, especially when it results inabdominal-visceral obesity, are key factors underlyinglong-term sympathetic activation and multiple featuresof the cardiometabolic syndrome. Lifestyle and publichealth measures have the potential to significantly reducethe prevalence of cardiometabolic risk factors and toslow the progression of the cardiovascular continuum.While there are data supporting sympatholytic therapyfor primary prevention of cardiovascular diseases, especiallyin younger and middle-aged men, the evidence forbeneficial effects of ß-blockers is more clearly establishedfor secondary prevention. Further research to identifyeffective pharmacological tools for the primary preventionof cardiometabolic risk factors and related clinicalcomplications is a priority given the growing globaldisease burden.
 
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REFERENCES
  1. Vasan RS, Levy D. The role of hypertension n the pathogenesisof heart failure. A clinical mechanistic view. Arch Intern Med1996 Sep;156(16):1789-1796.
  2. Brunzell JD, Ayyobi AF. Dyslipidemia in the metabolicsyndrome and type 2 diabetes mellitus. Am J Med 2003Dec;115(Suppl 8A):24S-28S.
  3. Levy RL, White PD, Stroud WD, Hillman CC. Transienttachycardia: prognostic significance alone and in associationwith transient hypertension. JAMA 1945 Oct;129(9):585-588.
  4. Carnethon MR, Yan L, Greenland P, Garside DB, Dyer AR,Metzger B, Daviglus ML. Resting heart rate in middle ageand diabetes development in older age. Diab Care 2008Feb;31(2):335-339.
  5. Julius S, Jamerson K. Sympathetics, insulin resistance andcoronary risk in hypertension: the 'chicken-and-egg' question.J Hypertens 1994 May;12(5):495-502.
  6. Facchini FS, Stoohs RA, Reaven GM. Enhanced sympatheticnervous system activity. The link between insulin resistance,hyperinsulinemia, and heart rate. Am J Hypertens 1996Oct;9(10 Pt 1):1013-1017.
  7. Palatini P, Julius S. Heart rate and the cardiovascular risk.J Hypertens 1997 Jan;15(1):3-17.
  8. Harburg E, Julius S, McGinn NF, McLeod J, Hoobler SW.Personality traits and behavioral patterns associated withsystolic blood pressure in college males. J Chronic Dis 1964May;17:405-414.
  9. Schneider RH, Egan BM, Johnson EH, Drobney H, Julius S.Anger and anxiety in borderline hypertension. PsychosomMed 1986 Mar-Apr;48(3-4):242-248.
  10. Marci CD, Glick DM, Loh R, Dougherty DD. Autonomic andprefrontal cortex responses to autobiographical recall of emotions.Cogn Affect Behav Neurosci 2007 Sep;7(3):243-250.
  11. Julius S, Pascual AV, London R. Role of parasympatheticinhibition in the hyperkinetic type of borderline hypertension.Circulation 1971 Sep;44(3):413-418.
  12. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevatedsympathetic nerve activity in borderline hypertensivehumans: evidence from direct intraneural recordings. Hypertension1989 Aug;14(2):177-183.
  13. Esler M, Jennings G, Lambert G. Noradrenaline release andthe pathophysiology of primary human hypertension. AmJ Hypertens 1989 Mar;2(3 Pt 2):140S-146S.
  14. Grassi G, Colombo M, Seravalie G, Spaziani D, Mancia G.Dissociation between muscle and skin sympathetic nerveactivity in essential hypertension, obesity, and congestiveheart failure. Hypertension 1998 Jan;31(1):64-67.
  15. Lund-Johansen, P. Hemodynamic alterations in early essentialhypertension: recent advances. In: Gross F, Strasser T,editors. Mild hypertension: recent advances. New York (NY):Raven Press; 1983. pp. 237-249.
  16. Julius S, Randall OS, Esler MD, Kashima T, Ellis C, Bennett J.Altered cardiac responsiveness and regulation in the normalcardiac output type of borderline hypertension. Circ Res 1975Jun;36(6 Suppl 1):199-207.
  17. Esler MD, Julius S, Randall OS, Ellis CN, Kashima T. Relationof renin status to neurogenic vascular resistance in borderlinehypertension. Am J Cardiol 1975 Oct;36(5):708-715.
  18. Esler M, Julius S, Zweifler A, Randall O, Harburg E, GardinerH, DeQuattro V. Mild high-renin essential hypertension:neurogenic human hypertension? N Engl J Med 1977Feb;296(8):405-411.


 
  1. Egan B, Panis R, Hinderliter A, Schork N, Julius S. Mechanismof increased α-adrenergic vasoconstriction in humanessential hypertension. J Clin Invest 1987 Sep;80(3):812-817.
  2. Egan BM, Schork NJ, Weder AB. Regional hemodynamicabnormalities in overweight men. Focus on alpha-adrenergicvascular responses. Am J Hypertens 1989 Jun;2(6 Pt 1):428-434.
  3. Kjeldsen SE, Moan A, Petrin J, Weder AB, Julius S. Effectsof increased arterial epinephrine on insulin, glucose andphosphate. Blood Press 1996 Jan;5(1):27-31.
  4. Julius S, Majahalme S. The changing face of sympatheticoveractivity in hypertension. Ann Med 2000 Jul;32(5):365-370.
  5. Feldstein C, Julius S. The complex interaction between overweight,hypertension, and sympathetic overactivity. J AmSoc Hypertens 2009 Nov-Dec;3(6):353-365.
  6. Hart MN, Heistad DD, Brody MJ. Effect of chronic hypertensionand sympathetic denervation on wall/lumen ratio ofcerebral vessels. Hypertension 1980 Jul-Aug;2(4):419-423.
  7. Bevan RD, Tsuru H, Bevan JA. Cerebral artery mass in therabbit is reduced by chronic sympathetic denervation. Stroke1983 May-Jun;14(3):393-396.
  8. Folkow B. Physiological aspects of primary hypertension.Physiol Rev 1982 Apr;62(2):347-504.
  9. Egan B, Schork N, Panis R, Hinderliter A. Vascular structureenhances regional resistance responses in mild hypertension.J Hypertens 1988 Jan;6(1):41-48.
  10. Guyton AC, Coleman TG. Quantitative analysis of thepathophysiology of hypertension. Circ Res 1969 May;24(Suppl 5):1-19.
  11. Guyton AC. Dominant role of the kidneys and accessoryrole of whole-body autoregulation in the pathogenesis ofhypertension. Am J Hypertens 1989 Jul;2(7):575-585.
  12. Kirchheim H, Ehmke H, Persson P. Sympathetic modulationof renal hemodynamics, renin release and sodium excretion.Klin Wochenschr 1989 Sep;67(17):858-864.
  13. DiBona GF. Sympathetic nervous system and hypertension.Hypertension 2013 Mar;61(3):556-560.
  14. Light KC, Koepke JP, Obrist PA, Willis PW 4th. Psychologicalstress induces sodium and fluid retention in men at high riskfor hypertension. Science 1983 Apr;220(4595):429-431.
  15. Harshfield GA, Dong Y, Kapuku GK, Zhu H, Hanevold CD.Stress-induced sodium retention and hypertension: a reviewand hypothesis. Curr Hypertension Rep 2009 Feb;11(1):29-34.
  16. Julius S, Jamerson K, Mejia A, Krause L, Schork N, Jones K.The association of borderline hypertension with target organchanges and higher coronary risk. Tecumseh Blood Pressurestudy. JAMA 1990 Jul;264(3):354-358.
  17. Huggett RJ, Scott EM, Gilbey SG, Bannister J, Mackintosh AF,Mary DA. Disparity of autonomic control in type 2 diabetesmellitus. Diabetologia 2005 Jan;48(1):172-179.
  18. Evans DJ, Murray R, Kissebah AH. Relationship betweenskeletal muscle insulin resistance, insulin-mediated glucosedisposal, and insulin binding. Effects of obesity and body fattopography. J Clin Invest 1984 Oct;74(4):1515-1525.
  19. Jamerson KA, Julius S, Gadbrandsson T, Andersson O,Brant DO. Reflex sympathetic activation induces acuteinsulin resistance in the human forearm. Hypertension 1993May;21(5):618-623.
  20. Jamerson KA, Smith SD, Amerena JV, Grant E, Julius S.Vasoconstriction with norepinephrine causes less forearminsulin resistance than a reflex sympathetic vasoconstriction.Hypertension 1994 Jun;23(6 Pt 2):1006-1011.

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  1. Lillioja S, Young AA, Culter CL, Ivy JL, Abbott WG, Zawadzki JK,Yki-Jarvinen H, Christin L, Secomb TW, Bogardus C. Skeletalmuscle capillary density and fiber type are possible determinantsof in vivo insulin resistance in man. J Clin Invest 1987Aug;80(2):415-424.
  2. Pollare T, Lithell H, Selinus I, Berne C. Application of prazosinis associated with an increase of insulin sensitivity inobese patients with hypertension. Diabetologia 1988 Jul;31(7):415-420.
  3. Berne C, Pollare T, Lithell H. Effects of antihypertensivetreatment on insulin sensitivity with special reference toACE inhibitors. Diabetes Care 1991 Nov;14(Suppl 4):39-47.
  4. Cohn JN. Relationship of plasma volume changes to resistanceand capacitance vessel effects of sympathomimeticamines and angiotensin in man. Clin Sci 1966 Apr;30(2):267-278.
  5. Julius S, Pascual AV, Reilly K, London R. Abnormalities ofplasma volume in borderline hypertension. Arch Intern Med1971 Jan;127(1):116-119.
  6. Greenwood JP, Scott EM, Stoker JB, Mary DA. Hypertensiveleft ventricular hypertrophy: relation to peripheral sympatheticdrive. J Am Coll Cardiol 2001 Nov;38(6):1711-1717.
  7. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ.Magnitude of left ventricular hypertrophy and risk of suddendeath in hypertrophic cardiomyopathy. N Engl J Med 2000Jun;342:1778-1785.
  8. Haider AW, Larson MG, Benjamin EJ, Levy D. Increasedleft ventricular mass and hypertrophy are associated withincreased risk for sudden death. J Am Coll Cadiol 1998Nov;32(5):1454-1459.
  9. Jouven X, Zureik M, Desnos M, Guerot C, Ducimetiere P.Resting heart rate as a predictive factor for sudden death inmiddle-aged men. Cardiovasc Res 2001 May;50(2):373-378.
  10. Gillman MW, Kannel WB, Belanger A, D'Agostino RB.Influence of heart rate on mortality among persons withhypertension: the Framingham Study. Am Heart J 1993Apr;125(4):1148-1154.

 
  1. Julius S, Palatini P, Kjeldsen SE, Zanchetti A, Weber MA,McInnes GT, Brunner HR, Mancia G, Schork MA, Hua TA,et al. Usefulness of heart rate to predict future cardiac eventsin treated patients with high-risk systemic hypertension. AmJ Cardiol 2012 Mar;109(5):685-692.
  2. Palatini P, Roawi W, Casiglia E, Chalmers J, Ferrari R, Grassi G,Inoui T, Jelakovic B, Jensen MT, Julius S, et al. Management ofthe hypertensive patient with elevated heart rate: Statementof the Second Consensus Conference endorsed by the EuropeanSociety of Hypertension. J Hypertens 2016 May;34(5):813-821.
  3. Benedict CR, Shelton B, Johnstone DE, Francis G, Greenberg B,Konstam M, Probstfield JL, Yusuf S. Prognostic significanceof plasma norepinephrine in patients with asymptomaticleft ventricular dysfunction. Circulation 1996 Aug;94(4):690-697.
  4. Grassi G, Seravalle G, Mancia G. Sympathetic activationin cardiovascular disease: evidence, clinical impact andtherapeutic implications. Eur J Clin Invest 2015 Dec;45(12):1367-1375.
  5. Cullington D, Goode KM, Zhang J, Cleland JG, Clark AL. Isheart rate important for patients with heart failure in atrialfibrillation? JACC Heart Fail 2014 Jun;2(3):213-220.
  6. Wikstrand J, HJalmarson A, Waagstein F, Fagerberg J, GoldsteinS, Kjekshus J, Wedel H; MERIT-HF Study Group. Doseof metoprolol CR/XL and clinical outcomes in patients withheart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure(MERIT-HF). J Am Coll Cardiol 2002 Aug;40(3):491-498.
  7. Yancy CW, Jessup M, Bozkurt B, Bulter J, Casey DE Jr,Colvin MM, Drazner MH, Filippatos GS, Fonarow GC,Givertz MM, et al. 2017 ACC/AHA/HFSA focused update ofthe 2013 ACCF/AHA guideline for the management of heartfailure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical PracticeGuidelines and the Heart Failure Society of America. J AmColl Cardiol 2017 Aug;70(6):776-803.

 
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