A Call to Action and a Lifecourse Strategy to Address the Global Burden of Raised Blood Pressure on Current and Future Generations: The Lancet Commission on Hypertension

Baroreflex Activation Therapy Lowers Blood Pressure in Patients With Resistant Hypertension Results From the Double-Blind, Randomized, Placebo-Controlled Rheos Pivotal Trial

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.

Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy

Many antihypertensive medications and lifestyle changes are proven to reduce blood pressure. Over the past few decades, numerous additional modalities have been evaluated in regard to their potential blood pressure-lowering abilities. However, these nondietary, nondrug treatments, collectively called alternative approaches, have generally undergone fewer and less rigorous trials. This American Heart Association scientific statement aims to summarize the blood pressure-lowering efficacy of several alternative approaches and to provide a class of recommendation for their implementation in clinical practice based on the available level of evidence from the published literature. Among behavioral therapies, Transcendental Meditation (Class IIB, Level of Evidence B), other meditation techniques (Class III, Level of Evidence C), yoga (Class III, Level of Evidence C), other relaxation therapies (Class III, Level of Evidence B), and biofeedback approaches (Class IIB, Level of Evidence B) generally had modest, mixed, or no consistent evidence demonstrating their efficacy. Between the noninvasive procedures and devices evaluated, device-guided breathing (Class IIA, Level of Evidence B) had greater support than acupuncture (Class III, Level of Evidence B). Exercise-based regimens, including aerobic (Class I, Level of Evidence A), dynamic resistance (Class IIA, Level of Evidence B), and isometric handgrip (Class IIB, Level of Evidence C) modalities, had relatively stronger supporting evidence. It is the consensus of the writing group that it is reasonable for all individuals with blood pressure levels >120/80 mm Hg to consider trials of alternative approaches as adjuvant methods to help lower blood pressure when clinically appropriate. A suggested management algorithm is provided, along with recommendations for prioritizing the use of the individual approaches in clinical practice based on their level of evidence for blood pressure lowering, risk-to-benefit ratio, potential ancillary health benefits, and practicality in a real-world setting. Finally, recommendations for future research priorities are outlined.

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Beyond Medications and Diet: Alternative Approaches to Lowering Blood Pressure A Scientific Statement From the American Heart Association

Evidence assembled in this review indicates that sympathetic nervous system dysfunction is crucial in the development of heart failure and essential hypertension. This takes the form of persistent and adverse activation of sympathetic outflows to the heart and kidneys in both conditions. An important goal for clinical scientists is translation of the knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this ‘ mechanisms to management ’ transition is at different stages of development with regard to the two disorders. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to the introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on the demonstration of activation of the renal sympathetic outflow. Additional evidence in this regard is provided by the results of pilot studies exploring the possibility to reduce blood pressure in resistant hypertensives through electrical stimulation of the area of carotid baroreceptors. Despite the general importance of the sympathetic nervous system in blood pressure regulation, and the specific demonstration that the blood pressure elevation in essential hypertension is commonly initiated and sustained by sympathetic nervous activation, drugs antagonizing this system are currently underutilized in the care of patients with hypertension. Use of beta-adrenergic blocking drugs is waning, given the propensity of this drug class to have adverse metabolic effects, including predisposition to diabetes development. The blood pressure lowering achieved with carotid baroreceptor stimulation and with the renal denervation device affirms the importance of the sympathetic nervous system in hypertension pathogenesis, and perhaps suggests a wider role for anti-adrenergic antihypertensives, such as the imidazoline drug class (moxonidine, rilmenidine) which act within the CNS to inhibit central sympathetic outflow, although the lack of large-scale outcome trials with this drug class remains a very material deficiency.

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The human sympathetic nervous system: its relevance in hypertension and heart failure

In animals, electric field stimulation of carotid baroreceptors elicits a depressor response through sympathetic inhibition. We tested the hypothesis that the stimulation acutely reduces sympathetic vasomotor tone and blood pressure in patients with drug treatment-resistant arterial hypertension. Furthermore, we tested whether the stimulation impairs the physiological baroreflex regulation. We studied 7 men and 5 women (ages 43 to 69 years) with treatment-resistant arterial hypertension. A bilateral electric baroreflex stimulator at the level of the carotid sinus (Rheos) was implanted > or =1 month before the study. We measured intra-arterial blood pressure, heart rate, muscle sympathetic nerve activity (microneurography), cardiac baroreflex sensitivity (cross-spectral analysis and sequence method), sympathetic baroreflex sensitivity (threshold technique), plasma renin, and norepinephrine concentrations. Measurements were performed under resting conditions, with and without electric baroreflex stimulation, for > or =6 minutes during the same experiment. Intra-arterial blood pressure was 193+/-9/94+/-5 mm Hg on medications. Acute electric baroreflex stimulation decreased systolic blood pressure by 32+/-10 mm Hg (range: +7 to -108 mm Hg; P=0.01). The depressor response was correlated with a muscle sympathetic nerve activity reduction (r(2)=0.42; P<0.05). In responders, muscle sympathetic nerve activity decreased sharply when electric stimulation started. Then, muscle sympathetic nerve activity increased but remained below the baseline level throughout the stimulation period. Heart rate decreased 4.5+/-1.5 bpm with stimulation (P<0.05). Plasma renin concentration decreased 20+/-8% (P<0.05). Electric field stimulation of carotid sinus baroreflex afferents acutely decreased arterial blood pressure in hypertensive patients, without negative effects on physiological baroreflex regulation. The depressor response was mediated through sympathetic inhibition.

Andreas M. Pichlmaier

Papers

Carotid Baroreceptor Stimulation, Sympathetic Activity, Baroreflex Function, and Blood Pressure in Hypertensive Patients