REVIEW Baroreflex activation therapy in hypertension JP Gassler and JD Bisognano The sympathetic nervous system is an effective homeostatic mechanism for modulating hemodynamics in times of stress and illness. Unfortunately, in some patients, this mechanism escapes physiologic control and through various mechanisms leads to resistant hypertension. Antihypertensive drug therapy is successful only to a point, leaving a significant percentage of patients nationwide with blood pressure measurements above guidelines despite being treated with at least three agents at maximally tolerated doses, consistent with a diagnosis of resistant hypertension. Novel methods of modifying the activity of the sympathetic nervous system have been studied in animals, and this review discusses the data in support of one of the techniques at the forefront of non-pharmacologic blood pressure therapy. Journal of Human Hypertension (2014) 28, 469–474; doi:10.1038/jhh.2013.139; published online 30 January 2014 Keywords: baroreflex; refractory; sympathetic nervous system modulation INTRODUCTION Hypertension awareness is so important that it was cited in 2012 as a Pan-American Health Organization (PAHO, a regional division of the World Health Organization) strategic target. Estimates from PAHO made on World Health Day, 7 April 2013, note that B9.4 million cardiovascular deaths worldwide can be attributed to hypertension, defined as a blood pressure greater than 140/90, and 1.9 million cardiovascular deaths in the Americas alone. Untreated hypertension can lead to atherosclerotic vascular disease, of the coronary or peripheral arteries, myocardial infarction, stroke, renal failure, cardiomyopathy and blindness. The American Heart Association (AHA) notes that the exact prevalence of resistant hypertension—defined as measured blood pressure above 140/90 despite being on at least three agents, one of which is a diuretic, at optimal doses—is unknown, but may be as high at 20–30%. 1 An analysis of the NHANES data from 1988 to 2008, by Dr Egan et al., 2 found that in the most recent time frame, from 2005 to 2008, 28% of patients with uncontrolled hypertension were on at least three agents, and therefore could be classified as apparent treatment-resistant hypertension. There have been recommendations for the diagnosis and management of hypertension since 1976, with the release of the Report of the Joint National Commission, long before most other diagnoses even began collecting data to create evidence-based management guidelines. Pharmacologic therapy and lifestyle changes currently are the predominant modalities utilized in the treatment of hypertension. One of the two principal approaches currently being evaluated for the device-based long-term treatment of hypertension involves subcutaneous implantation of a pacemaker-type device in the pectoral region; however, rather than stimulating the heart, it produces stimulation of the carotid sinus baroreceptors to reduce sympathetic output from the central nervous system. In this way, it is more akin to the Vagus Nerve Stimulator (Cyberonics, Houston, TX, USA), used in patients with complex partial epilepsy, to reduce seizure frequency by modulating central nervous system function. 3 HYPERTENSION PATHOPHYSIOLOGY Numerous factors and organs have a role in establishing an individual’s blood pressure. Cardiac contractility and heart rate have a direct role, as do vasomotor tone of the peripheral vasculature. In addition, neurohormonal controls arising from the kidneys, via renin secretion, and the adrenal glands, via secretion of norepinephrine and epinephrine, also have a role. Finally, the patient’s plasma volume, affected both by fluid status, but, more importantly in many patients, sodium loading, also has an inherent role in maintaining a hypertensive state. Here again, the kidneys are directly involved through their ability to provide both natriuresis and intravascular fluid volume reduction. The central nervous system exerts influence on several of these mediators of hypertension. These aspects can be directly affected by sympathetic stimulation from the central nervous system, notably with an increase in cardiac contractility and heart rate, as well as an increase in resistance arteriole constriction, or vasomotor tone. In addition, an increase in sympathetic stimula- tion induces a reduction in natriuresis and diuresis, with a concomitant increase in renin secretion. In the normally function- ing state, these mechanisms work to prevent hypotension in the setting of vasomotor collapse, such as in the setting of significant blood loss, or vasodilatation, such as that related to sepsis. SYMPATHETIC NERVOUS-SYSTEM-MODULATING THERAPY In many patients with hypertension, however, relative hyper- activity of the sympathetic nervous system can become mala- daptive and have a primary or permissive role in the sustaining of hypertension and related target organ system damage. Chronic sympathetic outflow leads to persistent blood pressure increases related to overstimulation of the above mechanisms (Figure 1). Many of the current drugs in our antihypertensive armamentarium are directed at some aspect of this system, including beta blockers, reducing the effects on myocardial contractility, alpha blockers, directed at reducing vasomotor tone, and angiotensin- converting enzyme inhibitors or angiotensin II receptor blockers, directed at the renin–angiotensin–aldosterone axis downstream of Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. Correspondence: Dr JD Bisognano, Professor of Medicine/Cardiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 601-7, Rochester, NY 14642, USA. E-mail: John_Bisognano@urmc.rochester.edu Received 7 May 2013; revised 11 November 2013; accepted 19 November 2013; published online 30 January 2014 Journal of Human Hypertension (2014) 28, 469–474 & 2014 Macmillan Publishers Limited All rights reserved 0950-9240/14 www.nature.com/jhh