Curr Hypertens Rep (2015)7:6 DOI 10.1007/s11906-015-0532-6
SECONDARY HYPERTENSION: NERVOUS SYSTEM MECHANISMS (J BISOGNANO, SECTION EDITOR)
Vagal Modulation of Hypertension Bradley W. Petkovich & Joshua Vega & Sabu Thomas
# Springer Science+Business Media New York 2015
Abstract Resistant hypertension despite compliance with pharmacologic therapies continues to hamper optimal blood pressure control. Vagal modulation via direct stimulation of the body’s parasympathetic nervous system is proving a promising therapeutic modality to help patients achieve their blood pressure goals. In this article, we review some of the key concepts of different vagal modulations for resistant hypertension including baroreflex activation therapy, renal sympathetic denervation, and direct vagal nerve stimulation. Keywords Vagal . Baroreflex activation . Renal denervation . Rheos . SYMPLICITY
Introduction Hypertension continues to be one of the major risk factors for cerebrovascular disease, coronary heart disease, congestive
This article is part of the Topical collection on Secondary Hypertension: Nervous System Mechanisms B. W. Petkovich : J. Vega Department of Medicine, University of Rochester at Strong Memorial Hospital, 601 Elmwood Ave, Box MED, Rochester, NY 14604, USA B. W. Petkovich e-mail: [email protected] J. Vega e-mail: [email protected] S. Thomas (*) Department of Medicine, Division of Cardiology, University of Rochester at Strong Memorial Hospital, 601 Elmwood Ave, Box MED, Rochester, NY 14604, USA e-mail: [email protected]
heart failure, and chronic renal disease. Despite advances in medical therapy, there remain a large number of patients who continue to remain hypertensive. As a result, novel modulators of the parasympathetic nervous system are now being employed to further control resistant hypertension. Classically, the autonomic nervous system is responsible for maintaining homeostatic conditions by modifying heart rate (HR), stroke volume (SV), and blood pressure (BP). However, in certain conditions such as myocardial infarction and in chronic heart failure, there appears to be an imbalance between the sympathetic and parasympathetic nervous system activity. In these states, it has been shown that an upregulation of sympathetic tone is associated with poorer outcomes [1, 2]. Surgical modification of the autonomic nervous system was first attempted in 1921 on humans using renal sympathectomy. Many studies from the 1930s cite renal sympathectomy as a means of treating essential hypertension with relatively favorable outcomes albeit with the apparent operative risks [3]. The development of better medications to treat hypertension generally obviated the role of surgery as a therapeutic option given its inherent upfront risks. With improvement in surgical technique and advancements in surgical technology, further roles for surgically modifying the body’s autonomic nervous system to control hypertension in select populations are now being revisited. This is especially true in patient with resistant hypertension—persons whose blood pressure remain elevated above goal despite the use of three or more antihypertensive agents to maximal doses [4]. The purpose of this article will be to review some of the recent studies that have investigated interventions of the autonomic nervous system to control blood pressure. This review will focus on baroreflex activation therapy (BAT), renal sympathetic denervation (RSD), and direct vagal nerve stimulation.
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Baroreflex Activation Therapy The body has several different mechanoreceptors that respond to stretch of the arterial, venous, and ventricular walls. While there exist reflex receptors in the atria, ventricles, and pulmonary vessels, the most prominent and well studied of the reflex mechanoreceptors of the body are those of the aorta and carotid sinuses. These mechanoreceptors respond to the stretch by sending signals that join the glossopharyngeal nerves of carotid baroreceptors (CN IX) to the nucleus tractus solitarius and nucleus ambiguus (of the medulla oblongata) before eventually being modified in the hypothalamus. The hypothalamus is then responsible for the increased parasympathetic efferent activities slowing HR and decreasing blood pressure. It is this reflex system that not only allows us to respond to increased salt load or fluid intake by lowering blood pressure but it is also the same system that prevents us from becoming orthostatic when standing. Utilizing this concept, baroreflex activation therapy first was performed using electrical impulses to the carotid body for normotensive and hypertensive dogs [5–7]. The concept then was further verified by demonstrating the blood pressure lowering effects of variable stimulation during carotid endarterectomy in humans [8]. To demonstrate the effectiveness of carotid stimulation, the Food and Drug Administration approved the first phase II clinical trial for baroreflex activation therapy (Rheos™ Feasibility Trial) to demonstrate the technique, safety, and immediate effectiveness [9]. This proof-of-concept study demonstrated the safety and efficacy of baroreflex devices in humans with a near linear voltage dose to blood pressure reduction in 10 patients. The follow-up to the Rheos™ Feasibility Trial was the Rheos™ Pivotal Trial that utilized a larger population group consisting of 265 patients with resistant hypertension this time however including a sham group. Both groups had the Rheos™ Implantable Generator System placed in bilateral carotid sinuses with the same technique outlined in the Rheos™ Feasibility Trial with both 6-month and 1-year follow-up periods. Group A had the device turned on post surgically while group B (sham group) was implanted with the device remaining off. Somewhat surprising were the results of dramatic drop in the systolic blood pressure in both the device-activated and sham groups at 6 months. There was a much larger drop in systolic blood pressure (SBP) among the sham group than expected. The drop in SBP was on average 17 mmHg in the sham group compared to 26 mmHg in the device-activated group (p value=0.03). This did not appear to be all for loss as both groups achieved even greater drops in SBP to 35 and 33 mmHg at 12 months for group A and at 6 months for group B, respectively. As two of the five prespecified end points (acute responders and safety) had not been reached in the Rheos Pivotal Trial, questions regarding
Curr Hypertens Rep62:71 )5 02(
long-term effectiveness, observer effect, and placebo effect remained [10]. Following the completion of the Rheos Pivotal Trial, 76 % of the 322 patients implanted with the Rheos System were deemed to be clinical responders [those patients whose goal SBP had been met (SBP ≤140 or ≤130 in diabetes or renal disease) or those who had dropped by 20 mmHg or more from device activation]. Among the active responder groups, there was an average drop in SBP/diastolic blood pressure (DBP) of 35/16 (p
SECONDARY HYPERTENSION: NERVOUS SYSTEM MECHANISMS (J BISOGNANO, SECTION EDITOR)
Vagal Modulation of Hypertension Bradley W. Petkovich & Joshua Vega & Sabu Thomas
# Springer Science+Business Media New York 2015
Abstract Resistant hypertension despite compliance with pharmacologic therapies continues to hamper optimal blood pressure control. Vagal modulation via direct stimulation of the body’s parasympathetic nervous system is proving a promising therapeutic modality to help patients achieve their blood pressure goals. In this article, we review some of the key concepts of different vagal modulations for resistant hypertension including baroreflex activation therapy, renal sympathetic denervation, and direct vagal nerve stimulation. Keywords Vagal . Baroreflex activation . Renal denervation . Rheos . SYMPLICITY
Introduction Hypertension continues to be one of the major risk factors for cerebrovascular disease, coronary heart disease, congestive
This article is part of the Topical collection on Secondary Hypertension: Nervous System Mechanisms B. W. Petkovich : J. Vega Department of Medicine, University of Rochester at Strong Memorial Hospital, 601 Elmwood Ave, Box MED, Rochester, NY 14604, USA B. W. Petkovich e-mail: [email protected] J. Vega e-mail: [email protected] S. Thomas (*) Department of Medicine, Division of Cardiology, University of Rochester at Strong Memorial Hospital, 601 Elmwood Ave, Box MED, Rochester, NY 14604, USA e-mail: [email protected]
heart failure, and chronic renal disease. Despite advances in medical therapy, there remain a large number of patients who continue to remain hypertensive. As a result, novel modulators of the parasympathetic nervous system are now being employed to further control resistant hypertension. Classically, the autonomic nervous system is responsible for maintaining homeostatic conditions by modifying heart rate (HR), stroke volume (SV), and blood pressure (BP). However, in certain conditions such as myocardial infarction and in chronic heart failure, there appears to be an imbalance between the sympathetic and parasympathetic nervous system activity. In these states, it has been shown that an upregulation of sympathetic tone is associated with poorer outcomes [1, 2]. Surgical modification of the autonomic nervous system was first attempted in 1921 on humans using renal sympathectomy. Many studies from the 1930s cite renal sympathectomy as a means of treating essential hypertension with relatively favorable outcomes albeit with the apparent operative risks [3]. The development of better medications to treat hypertension generally obviated the role of surgery as a therapeutic option given its inherent upfront risks. With improvement in surgical technique and advancements in surgical technology, further roles for surgically modifying the body’s autonomic nervous system to control hypertension in select populations are now being revisited. This is especially true in patient with resistant hypertension—persons whose blood pressure remain elevated above goal despite the use of three or more antihypertensive agents to maximal doses [4]. The purpose of this article will be to review some of the recent studies that have investigated interventions of the autonomic nervous system to control blood pressure. This review will focus on baroreflex activation therapy (BAT), renal sympathetic denervation (RSD), and direct vagal nerve stimulation.
26
Page 2 of 4
Baroreflex Activation Therapy The body has several different mechanoreceptors that respond to stretch of the arterial, venous, and ventricular walls. While there exist reflex receptors in the atria, ventricles, and pulmonary vessels, the most prominent and well studied of the reflex mechanoreceptors of the body are those of the aorta and carotid sinuses. These mechanoreceptors respond to the stretch by sending signals that join the glossopharyngeal nerves of carotid baroreceptors (CN IX) to the nucleus tractus solitarius and nucleus ambiguus (of the medulla oblongata) before eventually being modified in the hypothalamus. The hypothalamus is then responsible for the increased parasympathetic efferent activities slowing HR and decreasing blood pressure. It is this reflex system that not only allows us to respond to increased salt load or fluid intake by lowering blood pressure but it is also the same system that prevents us from becoming orthostatic when standing. Utilizing this concept, baroreflex activation therapy first was performed using electrical impulses to the carotid body for normotensive and hypertensive dogs [5–7]. The concept then was further verified by demonstrating the blood pressure lowering effects of variable stimulation during carotid endarterectomy in humans [8]. To demonstrate the effectiveness of carotid stimulation, the Food and Drug Administration approved the first phase II clinical trial for baroreflex activation therapy (Rheos™ Feasibility Trial) to demonstrate the technique, safety, and immediate effectiveness [9]. This proof-of-concept study demonstrated the safety and efficacy of baroreflex devices in humans with a near linear voltage dose to blood pressure reduction in 10 patients. The follow-up to the Rheos™ Feasibility Trial was the Rheos™ Pivotal Trial that utilized a larger population group consisting of 265 patients with resistant hypertension this time however including a sham group. Both groups had the Rheos™ Implantable Generator System placed in bilateral carotid sinuses with the same technique outlined in the Rheos™ Feasibility Trial with both 6-month and 1-year follow-up periods. Group A had the device turned on post surgically while group B (sham group) was implanted with the device remaining off. Somewhat surprising were the results of dramatic drop in the systolic blood pressure in both the device-activated and sham groups at 6 months. There was a much larger drop in systolic blood pressure (SBP) among the sham group than expected. The drop in SBP was on average 17 mmHg in the sham group compared to 26 mmHg in the device-activated group (p value=0.03). This did not appear to be all for loss as both groups achieved even greater drops in SBP to 35 and 33 mmHg at 12 months for group A and at 6 months for group B, respectively. As two of the five prespecified end points (acute responders and safety) had not been reached in the Rheos Pivotal Trial, questions regarding
Curr Hypertens Rep62:71 )5 02(
long-term effectiveness, observer effect, and placebo effect remained [10]. Following the completion of the Rheos Pivotal Trial, 76 % of the 322 patients implanted with the Rheos System were deemed to be clinical responders [those patients whose goal SBP had been met (SBP ≤140 or ≤130 in diabetes or renal disease) or those who had dropped by 20 mmHg or more from device activation]. Among the active responder groups, there was an average drop in SBP/diastolic blood pressure (DBP) of 35/16 (p
