Author + information
- ↵⁎Reprint requests and correspondence:
Dr. Michael R. Zile, Medical University of South Carolina, Division of Cardiology/Department of Medicine, Ashley River Towers, 25 Courtenay Drive, Room 7067, Charleston, South Carolina 29425
The development left ventricular hypertrophy (LVH) represents a critical milestone in patients with hypertensive heart disease (HHD). This structural remodeling and the associated abnormalities in diastolic function portend an increased risk of both mortal and morbid events (1–4). Treatment that results in the regression of LVH is associated with a reduction in these event rates (5–8). However, success in reversing LVH using existing pharmaceutical regimens has neither been uniform nor complete, particularly in patients with drug-resistant, refractory hypertension. Abnormalities in the autonomic nervous system appear to contribute to the resistance both to treatment and to the induction of structural remodeling (9,10). The role played by autonomic imbalance in patients with HHD serves to underscore the importance of the development of a series of novel management strategies that target autonomic modulation (Table 1). One such novel strategy is the use of renal artery denervation (RAD) in refractory hypertension.
Renal Artery Denervation
RAD, produced by catheter-based production of a spiral array of radiofrequency lesions in both renal arteries, has been shown to reduce blood pressure (BP) in patients with hypertension resistant to multiple drugs in 2 clinical trials (Symplicity [Renal Denervation in Patients With Uncontrolled Hypertension] I and II) (11,12). A third trial in patients with refractory hypertension, Symplicity III, has begun enrolling patients. In this issue of the Journal, Brandt et al. (13) report the results of an echocardiographic substudy from patients enrolled in Symplicity II. There were 2 key conclusions from this study: RAD treatment resulted in the reduction of LV mass and an improvement in diastolic function.
Effects on LV mass
RAD was associated with a decrease in LV mass by 13% after just 1 month of treatment and 17% after 6 months of treatment. These changes in LV mass caused the incidence of LVH to fall from 63% at baseline to 33% 6 months after RAD; however, the average LV mass for the patients treated with RAD did not reach normal, and some patients did not have regression of LVH. By contrast, LV mass tended to increase in the control group. Of note, patients without LVH at baseline had no significant decrease in LV mass, that is, atrophy did not occur. Because a number of pharmaceutical-based clinical trials have shown that the regression of LVH has led to an improved prognosis (5–8), it is anticipated that LVH regression induced by RAD will also be associated with a reduction in mortal and morbid events; however, to date, this remains an unproven hypothesis.
Effects on diastolic function
RAD was associated with an improvement in LV diastolic function as measured by Doppler indices of LV lengthening (increased mitral annular E′) and by reduction of left atrial dimension. By contrast, these measures of diastolic function became more abnormal in the control group. Taken together, these changes suggest that there was a decrease in left atrial and LV diastolic pressures. This effect is further substantiated by a 39% reduction in N-terminal pro–B-type natriuretic peptide, compared with only an 8% reduction in the control group.
RAD mechanisms of action
How does RAD cause the regression of LVH and the improvement in diastolic function? It seems likely that both a decrease in LV myocardial load and a decrease in activation of the sympathetic nervous system contribute to these outcomes for the following reasons. First, the decrease in LV mass 1 month after RAD was faster and larger than any previous study in which a pressure-overload state (hypertension or aortic stenosis) was removed. Second, even in the 6 RAD-treated patients that did not have a decrease in BP, there was a significant decrease in LV mass. Third, the extent to which RAD caused LV mass regression after 6 months was larger than might have been predicted based on previous pharmacological studies. For example, on average, drug treatment results in a 10% decrease in LV mass, whereas RAD caused a 17% decrease despite comparable decreases in BP (14% and 15%, respectively) (5–8).
It also seems likely that RAD caused the dramatic improvement in LV diastolic function through interdependent mechanisms that include the regression of LVH, lowering of systolic arterial load, and alterations in sympathetic activation.
Autonomic modulation strategies: future strategies and applications
Abnormalities in autonomic regulation with overactivation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) and reduced vagal tone contribute to the development and progression of both HHD and heart failure (HF) (9,10). Although current pharmacological treatment may block individual components of the sympathetic nervous system and RAAS overactivation, RAD may provide a more integrated approach to normalizing autonomic activity. By altering both afferent and efferent renal nerve signaling, RAD appears to decrease afferent sympathetic signals from the kidney to the brain, reducing systemic sympathetic activation, and to decrease efferent sympathetic signals from the brain to the kidneys, reducing vasoconstriction and RAAS activation (9,10).
In addition to RAD, other novel strategies to modulate the autonomic nervous system are being developed for the treatment of HHD and HF (Table 1). These include stimulation of the carotid baroreceptor, vagal nerve, and spine cord using implanted stimulators. Each of these technologies will have specific advantages and disadvantages, but all seem likely to have the potential for benefit in at least some patients with HHD.
Data are sufficient to suggest potential strengths and potential limitations with individual strategies. For example, RAD can be accomplished with a single invasive procedure that does not require ongoing treatment to cause autonomic modulation. The effects on BP are profound and sustained. Its success does not require patient compliance. By contrast, RAD cannot be done in the presence of renal artery stenosis, specific renal artery anatomy (2 or more renal arteries/kidney). RAD is not titratable, and cannot be terminated or reversed. Thus far, as indicated by data in the Symplicity II trial echocardiographic substudy, there have been no issues with persistent hypotension or myocardial atrophy (13). Whether renal artery reinnervation will eventually occur is not known.
Who should receive autonomic modulation treatment? Current data suggest that patients across the spectrum of HHD may represent reasonable target populations. These HHD patients include those with refractory hypertension, those with hypertensive LVH, and those with hypertension-induced HF. Even patients with hypertension that is not refractory to drug treatment may be future candidates. In these HHD patients, autonomic modulation could reduce cost of treatment and improve patient compliance. All HHD patients with HF, regardless of the ejection fraction (EF), may benefit. Caution should probably be applied to patients with HF and a reduced EF and restricted to those with a systolic BP >115 mm Hg. One particularly apropos application is in HHD patients with HF and a preserved EF; for this group of HF patients, there is no current guideline-based treatment to reduce morbidity and mortality.
RAD caused regression of LVH and improvement in diastolic function; the mechanisms responsible for these effects include both reduced LV load and the change in autonomic modulation itself. This and other autonomic modulation strategies hold enormous promise for the treatment of patients with hypertensive heart disease.
Dr. Zile receives grant support from the Department of Veterans Affairs Merit Review Program and the NHLBI; consulting fees from Medtronic, CVRx Gilead, Novartis Pharmaceuticals, Sanofi-Aventis, and Up-To-Date; and has received them in the past from Boston Scientific, St. Jude Medical, BMS, Merck, Pfizer, Johnson & Johnson, and ABIM. Dr. Little receives consulting fees from Medtronic, CVRx, BioControl Medical, Gilead, Amylin, Corassist, Ono Pharmaceuticals, and ABIM; has received them in the past from Boston Scientific; and receives grant funding from the NHLBI.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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