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Hypertension
Hypertension
HYP
Hypertension (Dallas, Tex. : 1979)
0194-911X
1524-4563
Lippincott Williams & Wilkins Hagerstown, MD

39136127
HYPE202219460
00004
10.1161/HYPERTENSIONAHA.123.19460
3
10001
10110
Reviews
Autonomic Nervous System: A Therapeutic Target for Cardiac End-Organ Damage in Hypertension
Gottlieb Lisa A. 1
https://orcid.org/0000-0002-4425-549X
Mahfoud Felix 2
https://orcid.org/0000-0002-4370-8135
Stavrakis Stavros 3
Jespersen Thomas 1
https://orcid.org/0000-0003-4893-0824
Linz Dominik 14
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (L.A.G., T.J., D.L.).
Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University Hospital, Homburg, Germany (F.M.).
Department of Internal Medicine, Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma City (S.S.).
Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, the Netherlands (D.L.).
Correspondence to: Dominik Linz, University of Copenhagen, Faculty of Health and Medical Sciences, Cardiac Physiology Laboratory, Panum Institue, Blegdamsvej 3B, 2200 Copenhagen. Email dominik.linz@sund.ku.dk
13 8 2024
10 2024
81 10 20272037
© 2024 The Authors.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

More than 1.5 billion people worldwide have arterial hypertension. Hypertension increases the risks of death and cardiovascular disease, such as atrial fibrillation and heart failure. The autonomic nervous system plays an essential role in hypertension development and disease progression. While lifestyle factors, such as obesity and obstructive sleep apnea, predispose to hypertension by increasing sympathetic activity, hypertension itself maintains the autonomic nervous imbalance, providing the substrate for atrial fibrillation and heart failure. Therefore, autonomic nervous system modulation either by direct targeting or indirect treatment of comorbidities has the potential to treat both hypertension and related atrial and ventricular end-organ damage. We discuss interventions for the modulation of the autonomic nervous system for hypertension and related cardiac end-organ damage, including pharmacological adrenergic beta-receptor blockade, renal denervation, carotid baroreceptor stimulation, low-level vagal stimulation, and ablation of ganglionated plexuses. In summary, the literature suggests that targeting the autonomic nervous system potentially represents a therapeutic approach to prevent atrial and ventricular end-organ damage in patients with hypertension. However, clinical trials specifically designed to test the effect of autonomic modulation on hypertension-mediated cardiac end-organ damage are scarce.

ablation therapy
atrial fibrillation
autonomic nervous system
heart failure
hypertension
OPEN-ACCESSTRUE
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pmcMore than 1.5 billion people worldwide have arterial hypertension, defined in adults as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg.1 Hypertension increases the risks of adverse cardiovascular outcomes and death.2 Conversely, lowering the blood pressure below <130 mm Hg prevents cardiovascular diseases and death.3 High blood pressure has long-term adverse effects on multiple organs, including the heart.4 Such hypertension-mediated cardiac end-organ damage often takes clinical form as atrial fibrillation (AF) and heart failure (HF).4

Despite being essential for regulating cardiovascular physiology, the autonomic nervous system (ANS) also plays a relevant role in the pathophysiology of hypertension.5 Hypertension is associated with increased sympathetic activity, attenuation of parasympathetic activity, and activation of the renin-angiotensin-aldosterone system that interacts with ANS. These ANS alterations not only increase blood pressure but also perpetuate the development of AF and HF.5–7 Common comorbidities, such as obstructive sleep apnea (OSA) and obesity, can contribute to altered ANS activity further accelerating the pathogenesis of hypertension, AF and HF.8,9

ANS modulation, therefore, represents a potential therapeutic target for both hypertension and related cardiac end-organ damage. Below, we discuss clinical interventions for ANS modulation in hypertension and related AF and HF (outlined in the Figure and Table 1). Most clinical trials have been designed to test outcomes in blood pressure and not to study potential preventative effects on end-organ damage in the heart (Tables 2 and 3). Despite reports with promising results, the current evidence levels for ANS modulatory treatments for AF and HF remain low and the treatments are not routinely recommended,23,24 implying a knowledge gap to be covered in future randomized trials. The role of ANS in the pathogenesis of hypertension, AF, HF, OSA, and obesity has been reviewed elsewhere.5–9

Table 1. Therapeutic Approaches for Autonomic Nervous Modulation

Table 2. Effects of Autonomic Modulation by Device Therapies on Hypertension and Related Cardiac End-Organ Disease

Table 3. Effect of Ablative and Surgical Autonomic Modulation on Hypertension and Related Cardiac End-Organ Disease

Figure. Therapeutic targets for autonomic modulation of hypertension and related cardiac end-organ damage. Baroreceptors located in the aortic arch and carotid sinus, which upon activation transmit a signal via afferent parasympathetic nerves to the central nervous system. Chemoreceptors exist in the carotid bodies near the bifurcation of the external and internal carotid arteries. Sympathetic nerves directly innervate the myocardium and connect with parasympathetic nerves in the ganglionated plexuses, located in the epicardial fat pads. Sympathetic nerves reach the renal artery. Renin is released in the kidneys upon adrenergic receptor activation. The autonomic nervous system can be targeted at multiple sites with disparate effects on cardiovascular (patho)physiology. CPAP indicates continuous positive airway pressure; and OSA, obstructive sleep apnea.

DIRECT PHARMACOLOGICAL ANS MODULATION

Several drugs have direct effects on ANS, potentially influencing hypertension and hypertension-mediated cardiac end-organ damage.

Adrenergic Beta-Receptor Blockade

Beta receptor antagonists (beta-blockers), either selectively acting on beta-1 receptors or nonselectively on both beta-1 and beta-2 receptors, are commonly used as antihypertensive agents, particularly in patients with serious cardiac indications.4 Noteworthy, the hypertension-related high sympathetic and reduced parasympathetic activity is not completely normalized with beta-blockade in patients with hypertension, despite a normalization in blood pressure.25

Beta-blockers are a cornerstone in HF treatment, reducing morbidity and mortality in patients with reduced ejection fraction.23 In patients with AF, beta-blockers can facilitate maintenance of sinus rhythm after electrical cardioversion.26 Previous European expert consensus statement on AF management suggested β-blocker therapy for sympathetic mediated AF.27 This is, however, not recommended in recent guidelines.24

Adrenergic Alpha-1 Receptor Antagonists

Alpha-1 receptor blockers (eg, doxazosin) are no longer recommended as first line agents for the treatment of hypertension.4 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed an increase in AF and HF incidence in the patient group treated with doxazosin compared with other antihypertensive drug classes.28,29 The ASCOT trial did not confirm this when doxazosin was given as third-line antihypertensive treatment.30 According to current guidelines, these agents may be utilized as reserve antihypertensive drugs in patients with resistant hypertension.4

Adrenergic Alpha-2 Receptor Agonists

Clonidine and moxonidine are commonly used alpha-2 receptor agonists, which predominantly inhibit sympathetic activity centrally and thus lowering blood pressure. These agents may be utilized as reserve antihypertensive drugs in patients with resistant hypertension.4 The randomized placebo-controlled MOXCON trial showed an increased mortality with moxonidine treatment (forced titration to 5× to 6× maximum dose commonly used in hypertension therapy) in patients with HF with reduced ejection fraction.31 The mechanisms involved in increased mortality with centrally mediated sympathetic inhibition by moxonidine in HF remain unclear and may be related to prevention of beneficial compensatory autonomic adaption, with the high drug dosages used, or the trial design.

In patients with concomitant hypertension and paroxysmal AF, the addition of moxonidine to standard antihypertensive treatment decreased diastolic but not the systolic blood pressure.32 The individual AF burden was lowered when the patients were treated with moxonidine.32 This antiarrhythmic effect may depend on a lower atrial pressure and an attenuated sympathetic effect.

Renin-Angiotensin-Aldosterone System Blockade

Antagonists of the angiotensin II receptor, angiotensin-converting enzyme, and mineralocorticoid receptor block renin-angiotensin-aldosterone system, thereby not only decreasing blood pressure but also sympathetic activity.33 Mineralocorticoid receptor antagonists have been shown to improve diastolic function in patients with HF with preserved ejection fraction but failed to improve morbidity and mortality.34,35 Moreover, treatment of hypertension with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers associates with a lower risk of incident AF when compared to β-blockers and diuretics.36 This emphasizes that an attenuation of the effects of angiotensin II in addition to control of blood pressure reduces the risk of AF, possibly by reduced sympathetic activity.

GLP-1R Agonists

GLP-1R (glucagon-like peptide-1 receptor) agonists induce a small increase in heart rate in humans (≈3 bpm),37 thereby questioning ANS modulation. However, a meta-analysis of data from 182 patients with diabetes reported unaltered heart rate variability by GLP-1R agonist treatment.37 On the other hand, in rodents, increases in heart rate and blood pressure by GLP-1R agonists were attenuated by propranolol administration.38 Future studies may reveal a GLP-1R agonist–mediated sympathetic response in humans, potentially making these drugs less favorable in the treatment of hypertension and related cardiac end-organ damage. However, a minor detrimental autonomic effect in the heart by GLP-1R agonists might be counterbalanced by the body weight reduction, which itself attenuates ANS activity. Recently, in patients with HF with preserved ejection fraction and obesity, one-year GLP-1R agonist treatment increased 6-minute walking distance and decreased body weight with a mean of 13%.39

Sodium-Glucose Cotransporter-2 Inhibitors

In addition to enhancing urinary glucose excretion and weight loss, SGLT2-i (sodium-glucose cotransporter-2 inhibitor) decreases both blood pressure and blood volume in patients.40,41 Because a concomitant heart rate increase is absent with SGLT2-i therapy, it has been suggested that these drugs attenuate sympathetic activity.42 This has not been confirmed in humans. It remains speculative whether SGLT2-i can serve as autonomic modulatory treatment for hypertension and related cardiac end-organ damage.

ANS MODULATION BY DEVICE THERAPY

Carotid Baroreceptor Stimulation and Modulation

Electrical Baroreflex Amplification

A first trial of electrical baroreflex amplification showed a tendency toward a lower systolic blood pressure after 6 months of stimulation (data in Table 2), while 26% of patients experienced procedure-related complications, including permanent facial nerve injury.10 A second-generation device had a lower rate of serious complications and caused a significant reduction in systolic blood pressure, but no complete normalization.11 Still, 98% of patients reported mild adverse events, such as discomfort, following device implantation.11 No randomized controlled trial is currently available with this new device in patients with resistant hypertension.

In patients with HF with reduced ejection fraction, electrical baroreflex amplification may increase 6-minute walking distance and patients’ quality of life.12 However, this study was not blinded and the outcomes could have been influenced by the study design. A larger ongoing randomized trial aims at testing the efficacy of baroreflex amplification in patients with HF not eligible for cardiac resynchronization therapy (https://www.clinicaltrials.gov; Unique identifier: NCT02627196).

Electrical baroreflex stimulation is shown to promote AF in pigs and the proarrhythmic changes were attenuated, but not abolished, after parasympathetic blockade with atropine.43 Indeed, parasympathetic activity is known to contribute to AF arrhythmogenesis.7 The effect of baroreflex stimulation on AF in patients is not yet described.

Endovascular Baroreflex Amplification

A significant reduction in blood pressure was observed 3 years after stent implantation for endovascular baroreflex amplification in 47 patients with resistant hypertension.13 However, the sympathetic activity seemed unaltered by the treatment.44 Results from randomized sham-controlled trials are lacking, but one trial is ongoing (https://www.clinicaltrials.gov; Unique identifier: NCT03179800), while another was terminated due to lack of enrollment (https://www.clinicaltrials.gov; Unique identifier: NCT02804087).

Baroreflex Modulation by Cardiac Pacing

Dual-chamber cardiac pacing can modulate the atrioventricular interval and thereby lower blood pressure, which is the rationale of the Backbeat Moderato pacing system. The pacemaker is programmed to alternate between short and long atrioventricular intervals, leading to reduced stroke volume as well as inhibiting a compensatory baroreflex.45

A first trial in patients with hypertension in the need of a pacemaker showed a reduction in blood pressure from day 1 to 6 months with the Backbeat stimulation protocol.14 The effect of chronic pacing with short atrioventricular intervals may be detrimental to the atria because atrial contraction against (partially) closed atrioventricular valves increases the atrial pressure and volume, potentially causing proarrhythmic effects.46 However, left atrial size was similar in patients after 6 months of Backbeat stimulation compared with controls.14

Recently, another cardiac pacing strategy mimicking respiratory sinus arrhythmia (heart rate acceleration and deceleration during inspiration and expiration, respectively) is shown to improve cardiac output in a sheep model of HF with reduced ejection fraction.47

Low-Level Vagal Nerve Stimulation

Despite the observation of both an immediate and long-term antihypertensive effect by vagal stimulation in rats,48 the effect of electrical tragus stimulation in patients with hypertension remains elusive. However, long-term tragus stimulation reduced the AF burden in patients with paroxysmal AF compared with sham stimulation.15 In patients with HF with preserved ejection fraction, tragus stimulation for 3 months is associated with improved left ventricular strain.16

Spinal Cord Stimulation (for HF Treatment)

In 15 patients with HF with reduced ejection fraction completing 6 months of thoracic spinal cord stimulation (24 hours daily), ejection fraction and patient’s quality of life increased.17 However, a similar trial in 66 patients, but with 12 hours daily electrical spinal cord stimulation, showed no changes.18 The therapeutic effect of spinal cord stimulation on hypertension and AF is unknown.

ABLATIVE AND SURGICAL ANS MODULATION

Renal Denervation

Several randomized, sham-controlled trials have demonstrated the blood pressure–lowering efficacy of renal denervation over 24 hours for both radiofrequency and ultrasound renal denervation in a broad spectrum of patients whose hypertension ranges from mild-to-moderate to severe and resistant.20 Subsequently, the 2023 European Society of Hypertension guidelines state that renal denervation can be considered as a treatment option in patients with preserved renal function who have uncontrolled blood pressure despite the use of antihypertensive drug combination therapy, or if drug treatment elicits serious side effects and poor quality of life.4

Because afferent renal sympathetic nerves communicate with the heart via the brain stem, renal denervation has potential protective effects on hypertension-related atrial and ventricular damage. A meta-analysis demonstrated a reduction of left ventricular mass but not in left atrial volume following renal denervation in patients with hypertension.49 Nevertheless, in patients with concomitant AF and hypertension, renal denervation in addition to pulmonary vein isolation for AF was superior in preventing AF recurrence compared with pulmonary vein isolation alone.21 In addition to ANS changes, a lower blood pressure also leads to a reduced stretch of the atrial myocardium, thereby exerting an antiarrhythmic effect protecting against stretch-related AF.46

In 164 patients with resistant hypertension, renal denervation improved left ventricular diastolic relaxation in patients classified as having HF with preserved ejection fraction compared with patients without HF, despite similar changes in blood pressure.50 Randomized, blinded, and sham-controlled trials of renal denervation in patients with HF with reduced ejection fraction ((www.clinicaltrials.gov: NCT04947670) and with preserved ejection fraction ((www.clinicaltrials.gov: NCT05715697) are ongoing.

Carotid Body Ablation

In a proof-of-concept study in 15 patients with resistant hypertension, unilateral carotid body ablation did not significantly reduce the blood pressure.51 However, unilateral or bilateral surgical carotid body resection decreased the sympathetic activity and increased the tolerated exercise time in 10 male patients with HF with reduced ejection fraction, suggesting a therapeutic effect on the HF-related high sympathetic drive.52 This technique is not recommended in most recent guidelines on hypertension therapy.4

Stellate Ganglion Modulation (for AF Treatment)

Surgical resection of stellate ganglia to modulate atrial arrhythmias, but not hypertension nor HF, has been investigated. In patients with AF scheduled for ablation therapy, immediate AF inducibility was equally reduced by either temporary right or left stellate ganglion block.53 However, in patients with structural heart disease, bilateral stellate ganglion resection did not alter atrial arrhythmic burden.54

Ganglionated Plexus Modulation (for AF Treatment)

Ganglionated Plexus Ablation

Due to their localization, ganglionated plexuses may be unintentionally injured during pulmonary vein ablation for treatment of AF, ultimately having antiarrhythmic effects. A sustained rise in heart rate and attenuation of heart rate variability more often occurs in patients successfully treated for AF by ablation, indicating an antiarrhythmic effect of long-term parasympathetic denervation.55 Also, a high level of S100B, a marker of neural injury, immediately after pulmonary vein isolation is associated with less AF in patients during the early months after the ablation therapy.56

Therefore, the antiarrhythmic effect of direct targeting of the ganglionated plexuses by ablation has been studied. An early trial showed superiority in AF prevention with additional ganglionated plexus ablation compared with sole pulmonary vein isolation.22 However, a surgical ablation approach had similar success rates but more serious complications, such as major bleeding, in patients with additional ganglionated plexus ablation.57 The current guidelines do not recommend routine ganglionated plexus ablation in patients with AF undergoing ablation.24 However noteworthy, the standard pulmonary vein isolation procedure by cryo- and radiofrequency energy inadvertently injures at least 3 of the major atrial ganglionated plexuses.22 The extent to which this inadvertent modulation of the ANS contributes to long-term sinus rhythm maintenance remains to be determined.

Botulinum Toxin

Due to its transient effect, botulinum toxin injection into epicardial fat pads (containing ganglionated plexuses) has been tested as potential therapeutic option for perioperative AF. A recent trial reports similar rates of perioperative AF after open-heart surgery in patients without known AF, randomized to either botulinum toxin injection or placebo.58 In 60 patients with paroxysmal AF, botulinum toxin injection caused less AF during the first perioperative month, whereas no effect was observed in 145 patients with and without AF.59,60

ANS MODULATION BY MODIFICATION OF RISK FACTORS FOR HYPERTENSION

OSA Treatment

Nocturnal continuous positive airway pressure treatment is recommended in patients with OSA with severe daytime sleepiness or concomitant hypertension and reduces the number of apneic events during sleep.61 This mediates a reduction in central sympathetic activity and sometimes also blood pressure.62,63 It is, therefore, not surprising that continuous positive airway pressure treatment in patients with OSA and AF increased the antiarrhythmic effect of AF ablation.64 Likewise in patients with OSA and HF with reduced ejection fraction, continuous positive airway pressure therapy improved ventricular ejection fraction and decreased the urinary excretion of noradrenaline, the latter indicating an attenuation in sympathetic activity.65

Weight Loss in Overweight

A nonpharmacological weight loss by caloric restriction and exercise of 5 kg in overweight individuals reduced the systolic/diastolic blood pressure by 4.4/3.6 mm Hg.66 The blood pressure changes occurred both after short-term (<1 month) and long-term (>3 months) caloric restriction.67 Nevertheless, a reduction in sympathetic nerve activity only occurred with long-term caloric restriction.67 Long-term intentional weight reduction is shown to reduce AF burden in overweight patients subjected to either ablation or antiarrhythmic drugs.68

Exercise

While regular exercise triggers a homeostatic state of low sympathetic and high parasympathetic activity, a rapid increase in sympathetic activity occurs as an immediate response to exercise (exercise pressor reflex). Patients with hypertension often have an augmented blood pressure increase during exercise compared with normotensive individuals, despite antihypertensive treatment and controlled blood pressure in resting conditions.69 However, regular aerobic exercise reduced systolic and diastolic pressures in both patients with hypertension and healthy individuals.4 Three weekly 1-hour exercise sessions for 4 months reduced the sympathetic activity and normalized the baroreflex sensitivity in patients with hypertension with averaged normal weight.70

In patients with HF with reduced ejection fraction, high-intensity interval training, among other exercise strategies, improved the ejection fraction.71 Regular exercise of moderate intensity also decreased the AF burden in patients with known AF, whereas excessive high-intensity training is associated with the occurrence of AF in athletes, the latter most likely due to proarrhythmic parasympathetic activity.24

Dietary Sodium Restriction

A meta-analysis of 85 studies reports an approximately linear relation between dietary sodium intake and systolic and diastolic blood pressures in normotensive individuals and in patients with hypertension.72 The current guidelines on hypertension recommend a dietary intake of sodium restricted to <100 mmol (≈5.8 g sodium chloride) per day.4 A high dietary sodium intake is considered to enhance sympathetic activity, likely mediated by the brainstem. Direct infusion of sodium into cerebrospinal fluid elevated blood pressure and increased sympathetic activity in the adrenal glands of rodents.73 Accordingly, a high sodium intake is associated with high levels of plasma norepinephrine in patients with salt-sensitive hypertension.74 It is unknown whether ANS modulation by dietary sodium restriction influences HF and AF. However, sodium restriction is recommended in patients with HF to reduce congestive symptoms, likely by attenuating fluid retention.23

DISCUSSION AND FUTURE DIRECTIONS

Numerous clinical trials have investigated the efficacy and safety of autonomic modulatory therapies for hypertension and renal denervation is now recommended for clinical use in certain patients with hypertension by current guidelines.4 Because hypertension promotes cardiac end-organ damage, also mediated by ANS changes, autonomic modulatory therapies likely are beneficial for hypertensive patients with AF and HF. Tables 2 and 3 summarize the major trials, some with promising results for treating AF and HF. However, there is still a need for randomized and controlled trials on ANS modulation in AF and HF cohorts to cover current evidence gaps.23,24 It would be important to include control groups subjected to antihypertensive treatments causing similar reduction in blood pressure, to evaluate the direct role of autonomic modulation on cardiac end-organ prevention, independent of the hemodynamic load exerted on the heart.

Because sex has been shown to influence the effect of cardiovascular therapies with typically poorer outcomes in females,75 it is worth noticing that 8 of the 12 interventional clinical trials summarized in Tables 2 and 3 report on a male-dominant patient population. Achieving balanced patient populations, also in terms of racial ethnicity, is crucial in future trials, to ensure evidence-based medicine in all patient groups.

In alignment, pharmacological antihypertensive treatment, that normalizes blood pressure, does not show a complete normalization in ANS activity.25 This persisting autonomic dysfunction could favor progression of hypertension-related AF and HF, despite controlled hypertension with normal blood pressure. Direct modulation of ANS might result in a more effective prevention of hypertension-mediated end-organ damage in the heart than conventional antihypertensive drugs. However, it is still unknown whether autonomic modulatory therapies in patients with hypertension, but without AF and HF, prevent the later development of cardiac end-organ damage. Long-term follow-up of the clinical trials is essential to reveal such prevention in disease development of AF and HF in patients with hypertension. Last, combinations of pharmacological and interventional therapies with most optimal effect on ANS and cardiac end-organ damage remain to be identified.

ARTICLE INFORMATION

Sources of Funding

Danish Cardiovascular Academy (NNF20SA0067242) and BRIDGE II grant (NNF20SA0064340) provided funding to L.A. Gottlieb. Novo Nordisk Foundation Tandem Programme (NNF18OC0031634) provided funding to T. Jespersen; Novo Nordisk Foundation Young Investigator Awards 2021 (NNF21OC0066480) was given to D. Linz.

Disclosures

None.

Nonstandard Abbreviations and Acronyms

AF atrial fibrillation

ANS autonomic nervous system

GLP-1R glucagon-like peptide-1 receptor

HF heart failure

OSA obstructive sleep apnea

SGLT2-i sodium-glucose cotransporter-2 inhibitor

For Sources of Funding and Disclosures, see page 2035.
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