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Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited
IJCA-14413; No of Pages 5 International Journal of Cardiology xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited Guang-Ming Tam a, Bryan P. Yan a, Sharad V. Shetty b, Yat-Yin Lam a,⁎ a b
Prince of Wales Hospital, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong Royal Perth Hospital, Australia
a r t i c l e
i n f o
Article history: Received 21 December 2011 Accepted 22 January 2012 Available online xxxx Keywords: Transcatheter renal denervation Resistant hypertension Sympathetic nervous system
a b s t r a c t Resistant hypertension, defined as the failure to achieve target blood pressure despite concurrent use of 3 antihypertensive agents of different classes, is estimated to affect 20–30% of hypertensive patients. These patients are vulnerable to cardiovascular, cerebrovascular and renal complications. There is ample evidence that sympathetic nervous system hyperactivity contributes to the initiation, maintenance and progression of hypertension. The renal sympathetic nervous system, in particular, has been identified as a major culprit for the development and progression of hypertension, heart failure and chronic kidney disease in both preclinical and human studies. Traditional surgical sympathectomy proposed in 1940s was halted due to unacceptable operative risk and the emergence of anti-hypertensive medications. Recently, catheter-based renal sympathetic denervation by radiofrequency ablation has shown encouraging intermediate-term results with minimal complications in patients with resistant hypertension. This review summarizes the patho-physiological role of the renal sympathetic nervous system and the potential application of renal denervation therapy for the treatment of resistant hypertension. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hypertension is a common health problem that affects millions of people in the world [1,2]. Poorly controlled blood pressure (BP) leads to cardiovascular, cerebrovascular and renal complications. Despite the availability of multitudes of anti-hypertensive drugs, the percentage of patients achieving optimal control of hypertension has remained disappointingly low [1,2]. Resistant hypertension is defined as the failure to achieve target BP despite concurrent use of 3 antihypertensive drugs of different classes, with one of them being diuretics [3]. The reported prevalence of this condition ranged from 5 to 30% [4]. There are many factors contributing to resistant hypertension such as poor medication adherence, inappropriate drug combination, inadequate dosing, or the presence of secondary causes for hypertension in particular primary hyperaldosteronism, obstructive sleep apnea and chronic kidney disease. However, such factors are not found in the majority of resistant hypertension patients who have activated sympathetic nervous system (SNS) and increased sympathetic outflow. Lifestyle modification, enhancing drug compliance, treating of secondary causes or adding mineralocorticoid receptor antagonist such
⁎ Corresponding author at: Division of Cardiology, SH Ho Cardiovascular and Stroke Centre, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong. Tel.: + 852 26321299; fax: + 852 26373852. E-mail address: [email protected] (Y.-Y. Lam).
as spironolactone or eplerenone are well established strategies to treat resistant hypertension. Recently, catheter-based renal sympathetic denervation by radiofrequency ablation has shown encouraging results with minimal complications in patients with resistant hypertension. This procedure is a safer version of radical surgical sympathectomy which was proposed in the 40s and 50s when therapeutic options for hypertension were limited. This review summarizes the patho-physiological role of the renal SNS and the potential application of renal denervation therapy for the treatment of resistant hypertension and other diseases such as heart failure and chronic kidney disease. 2. Sympathetic nervous systems in hypertension Sympathetic innervations are responsible in the homeostasis mechanism of multiple systems, and overactivities of the SNS have many detrimental effects on various conditions (Fig. 1). In patients with hypertension, there are evidences of sympathetic overactivities as measured by the norepinepherine spill over and increased nerve firing rates in postganglionic sympathetic fibres in skeletal muscle [5]. The increase sympathetic activities contribute to the development of hypertension through the regulatory mechanism on rennin release, alternation of glomerular filtration rate, sodium retention and on cardiac pumping. In addition, SNS overactivities in hypertension have other possible adverse consequences. In the heart, SNS overactivities can cause arrhythmia, and its trophic effect contributes to the development of left ventricular hypertrophy [6]. In the liver, it
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.01.048
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
2
G.-M. Tam et al. / International Journal of Cardiology xxx (2012) xxx–xxx Systemic SNS activation.
Increase cardiac output, arrthymia, left ventricular hypertrophy.
hyperlipidaemia
vasopressin and oxytocin release Insulin resistance, impaired glucose metabolism.
Efferent sympathetic activations.
Increase sodium pump activity.
Afferent sympathetic activations
Increase vascular pressure renal ischemia renal artery occlusion
Renin secreting juxtaglomerular cells Preglomerular vasoconstriction
Fig. 1. Renal sympathetic innervation and relationship to systemic sympathetic system. SNS = sympathetic nervous system.
causes hyperlipidaemia by retarding postprandial clearing of lipids, and causes insulin resistance and hyperinsulinemia by impairing glucose delivery to muscle [7].
ureteropelvic pressure. The chemoreceptors are activated by concentrated substrates and respond to renal ischemia or renal artery occlusion (Fig. 1) [12].
3. Renal sympathetic innervations
4. Renal sympathetic denervation
3.1. Efferent system
It has been long postulated that systemic sympathetic nervous activation plays an important role in the perpetuation of hypertension, and previous human clinical work has shown that nephrectomy in end-stage renal failure patients resulted in reduction of muscle sympathetic nerve activity and calf vascular resistance [13]. Historically, non-selective surgical sympathectomy, often called ‘splanchnicectomy’ as it involved abdominal organs, was performed in patients with severe or malignant hypertension in the era where effective antihypertensive therapy was lacking. In these patients, surgery reduced sympathetic outflow to the kidneys, increased natriuresis and diuresis, and decreased renin release, without adversely affecting other functions of the kidney. While effective in reducing BP and improving survival, splanchnicectomy is a major surgery requiring a specialized expertise, prolonged hospital stay and has many adverse effects such as orthostatic hypotension, orthostatic tachycardia, palpitation, breathlessness, anhidrosis, cold hands, intestinal disturbance, and erectile dysfunction. These adverse effects can be attributed to the non-specific sympathetic denervation of the viscera and the vasculature of the peripherals [14]. Building on the concept of surgical sympathectomy to control hypertension, a novel catheter-based endovascular renal artery sympathetic denervation has been developed in recent years.
The efferent sympathetic fibers of renal sympathetic nervous system originate from the thoracic and lumbar sympathetic trunk. From there, they reach the T13-L1 ipsilateral and contralateral paravertebral ganglia and the prevertebral superior mesenteric and celiac ganglia. The postganglionic nerve fibers then run alongside the renal artery and enter the hilus of the kidneys, and from there they divide into smaller bundles and penetrate the cortical and juxtamedullary area alongside small blood vessels [8]. The activation of these sympathetic fibers has several effects. Firstly, the release of norepinephrine from renal sympathetic nerve terminals stimulates the postsynaptic alpha-1 adrenoceptors located on the basolateral membrane of renal tubular epithelial cells and results in an increase in activity of the sodium pump, which increases transepithelial sodium transport. Secondly, the direct activation of beta-1 adrenoceptors on juxtaglomerular granular cells releases renin and causes antinatriuresis. Finally, renal sympathetic activation produces preferential preglomerular vascular smooth muscle cells contraction and decreases renal blood flow and glomerular filtration rate (Fig. 1) [9–11]. 3.2. Afferent system
5. Transcatheter renal denervation (Table 1) Renal afferent nerves start from the renal pelvic wall, exit along the renal artery and extend to ipsilateral dorsal root ganglia. Their activation contributes directly to systemic hypertension by modulating central sympathetic nervous system activity and promoting vasopressin and oxytocin release from the neuro-hypophysis. There are 2 types of afferent receptors in the renal pelvis. The mechanoreceptors respond to increases in renal arterial or venous pressures or
This technique utilizes a radiofrequency ablation catheter (Symplicity® by Medtronic Inc., Minneapolis, MN, USA) which is introduced into each renal artery via femoral arterial access. Up to 6 discrete low-power radiofrequency ablations of 8 Watts or less lasting up to 2 min each is applied separated both longitudinally and rotationally within each renal artery (Fig. 2). The aim of ablation is
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
G.-M. Tam et al. / International Journal of Cardiology xxx (2012) xxx–xxx
3
Fig. 2. The Symplicity® catheter is a 5 French catheter specifically designed for renal sympathetic denervation. It is inserted through femoral artery and is positioned at the lumen of the renal artery. The catheter is then connected to a proprietary radiofrequency generator with built-in safety algorithms for delivering the therapy (a). Selective renal arteriogram is performed before the procedure with the aid of a dedicated guiding catheter (b). A total of 4 to 6 radiofrequency ablations would be delivered in an interrupted, spiral fashion within the renal artery (c). The arrow indicates the tip of the denervation catheter.
to disrupt the renal nerves located at the adventitia of these arteries which has been shown to effectively reduce renal norepinepherine spillover [15]. Optimal site for ablation is determined by contact impedance between the catheter tip and vessel wall. During ablation, tip temperature and impedance is monitored by the catheter system altering radiofrequency energy delivery in response to a predetermined algorithm. Adequate ablation is determined by significant drop in contact impedance after each ablation. There is no objective measure of procedural success at the time of procedure because the therapeutic effect of renal denervation in BP lowering is delayed up to 3 months (Table 1). This new technique has several advantages over the traditional surgical sympathectomy. Firstly, it is minimally invasive, and has a short procedural and recovery time. Secondly, it is selective and specific, hence avoiding the systemic adverse effects of surgical sympathectomy. Thirdly, as endovascular procedure and radiofrequency ablation are routinely practiced by interventional radiologists and cardiologists, this new catheter-based procedure can be assumed to be widely adaptable. Preclinical studies of this catheter-based procedure by Medtronic Inc. in juvenile swine reported comparable reduction in sympathetic activity to direct surgical sympathectomy, and the catheter-based procedure resulted in no renal arterial stenosis or thrombosis, nor gross or microscopic abnormalities in the kidney, surrounding stroma, or urinary bladder 6 months post procedure. Microscopically, only fibrosis of 10–25% of the total media and underlying adventitia, with mild disruption of the external elastic lamina was observed in the renal artery, with no significant smooth muscle hyperplasia or inflammatory components noted [16]. The first human study of catheter-based renal denervation was published as a proof-of-principle cohort study by Krum H. et al. This study aimed to assess the safety and the effectiveness of renal denervation in 45 patients with resistance hypertension and suitable renal arterial anatomy. In this study, renal denervation resulted in a significant and sustained BP reduction at one year [15]. Subsequent longerterm follow-up data of the studied cohort demonstrated durability of
BP reduction of up to 24 months [17]. In 10 of the patients, renal norepinepherine spillover was also measured after the procedure and was shown to be reduced by 47%. Peri-procedural and long-term safety was another endpoint being assessed in this study. Peri-procedural complication was observed in 2 cases in this study population, and 2 others in the later-published longer-term report. With the exception of 1 renal artery dissection occurring before the procedure, all of these complications were related to pseudoaneurysm or hematoma formation at the femoral arterial puncture sites. There was no renovascular complication occurring immediately after the procedure on renal angiographic studies and at 6 months of follow-up scans. There was a gradual decline in estimated glomerular filtration rate (eGFR) at 6 months (− 1.6 ML/min) and at 24 months of follow-up (−16.0 ML/min). However, the rate of decline is less than would be predicted based on natural history studies [18], and some of these patients had spironolactone or other diuretics added after the procedure, which might contributed to the decline in eGFR. In any case, eGFR data were only available in 10 patients at 24 months, and thus were not representative. The major limitation of this study is that it has no control group with which to make comparison regarding BP response and eGFR changes to. The term ‘resistant hypertension’ in this study was loosely defined and lacked proper investigation such as ruling out white-coat syndrome, or secondary hyperaldosteronism. Nevertheless this proof-of-principle study and its subsequent longer-term follow-up report have provided preliminary evidence that catheter-based renal denervation is a safe and effective technique with durable BP lowering effect. These data paved the way for the subsequent randomized controlled trial – the Symplicity HTN-2 Trial. The Symplicity HTN-2 Trial was conducted in a larger population of 106 patients, using the same inclusion criteria as in the pioneer study. These 106 patients were randomized into renal denervation group or to control group (maintenance of previous medical treatment alone). At 6 months, there was a significant reduction of office based BP by 33/11 mmHg when comparing with the control group.
Table 1 Completed clinical studies [14,19–21] on transcatheter renal denervation therapy. Author/trial acronyms
Sample size
Mean change in BP at 6 months (systolic/diastolic)
Important findings
Krum et al. Symplicity HTN-2
45 106
− 22/−11 mmHg − 32/−12 mmHg
Mahfoud et al.
50
− 32/−12 mmHg*
Witkowski et al.
10
− 34/−13 mmHg
Renal denervation produces significant BP reduction without serious adverse events. Renal denervation is safe and effective in producing substantial BP reduction as compared to medical treatment alone In addition to BP reduction, renal denervation also improves glucose metabolism and insulin sensitivity. In addition to BP reduction, renal denervation also improves glycemic control and reduces sleep apnea severity.
*3-month results. BP = blood pressure.
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
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G.-M. Tam et al. / International Journal of Cardiology xxx (2012) xxx–xxx
The reduction of BP was still significant after taking into account the effects of medication adjustment and on 24 h ambulatory BP monitoring. There were 5 hospital admissions for hypertensive emergency during the study period: 3 in the renal denervation group and 2 in the treatment group. The authors also reported 5 serious adverse events in both the renal denervation (1 transient ischemic attack and 1 angina requiring a coronary stent) and control (2 transient ischemic attacks and 1 angina requiring stenting) groups. There was no serious complication related to the procedure. There was no significant difference in the decline of eGFR or reno-vascular complications either between the 2 groups [19]. While confirming the findings in the pioneer study, this randomized trials shared the same limitations of having a relatively small sample size and a short follow-up period for the assessment of composite cardiovascular events. To address these issues, the Symplicity HTN-3 trial which is a multi-center, larger-scaled, randomized, controlled study including a sham procedure in the control group is currently underway. Similar to the first study, the Symplicity HTN-2 Trial did not clearly define the ‘resistant hypertension’ either, and did not exclude the possibilities such as secondary hypertension. Moreover, the baseline characteristics of patients were different between the 2 groups, with the renal denervation group having more males (65% vs. 50%), higher rates of diabetes (40% vs. 28%) and higher prevalence of coronary artery disease (19% vs. 7%). These differences might indicate more serious cases of hypertension in the renal denervation group and skewed the result in favor of the control group. In spite of these limitations, this trial adds strong evidence supporting the effectiveness and safety of catheter-based renal denervation [19]. In addition to significant BP reduction, renal denervation was also shown to be effective in the treatment of other conditions coexisting with resistant hypertension. In a small study, renal denervation was shown to improve glucose metabolism by reducing the fasting glucose level and insulin sensitivity by decreasing insulin level and Cpeptide level, on top of a significantly reducing BP [20]. Another non-randomized, open-label study even demonstrated an improvement of sleep apnea severity in patients treated with renal denervation, as well as BP reduction and blood glucose control [21]. 6. Other minimally-invasive approaches for Sympathetic Inhibition Other minimally invasive treatments of hypertension aiming at sympathetic nervous system inhibition have also received attention recently. Among them is the carotid baroreceptor activation therapy. The concept was based on the assumption that the continuous carotid nerve stimulation causes sympathetic inhibition as the body senses a constant rise in blood pressure, and this subsequent will result in BP reduction. This approach involves implanting an external pulse generator, the Rheos device, which connects to 2 electrodes leads that are placed at the perivascular space of carotid sinus [22]. While showing promising results in animal models as well as in the early feasibility study [23], this approach failed to achieve satisfactory BP control or safety end points in the recent published randomized controlled trial [24]. Another potential approach is the deep brain stimulation which stimulates ventrolateral periaqueductal gray and periventricular gray areas and evokes hypotension associated with peripheral vasodilatation indicating a sympathetic inhibition. The original intend of this approach is for pain relief, but it was also demonstrated to have hypotensive effect in a subject with refractory hypertension [25].
of norepinepherine was increased in patient with heart failure, and that the prognosis of patient with heart failure was related to plasma concentration of norepinepherine [26]. In patients with hepatic cirrhosis and portal hypertension, it has been shown that the norepinephrine spillover to plasma was higher from the hepatomesenteric circulation and from the renal circulation [27]. These sympathetic overactivities will probably promote sodium retention, increase the post-sinusoidal resistance and perpetuate portal venous hypertension. The benefits of sympathetic inhibition have been long established in the 2 aforementioned conditions. In portal hypertension, administer of clonidine has shown to reduced the post-sinusoidal vascular resistance [27] and use of beta-blocker has been shown to prevent variceal bleeding and refractory ascites [28]. In patients with heart failure, the beneficial effects of sympathetic inhibitions are even more robust. Numerous studies have shown that the use betablocking agents provide survival advantages in patient with heart failure [29]. Minimally-invasive sympathetic inhibition such as renal denervation therefore might be beneficial in patients with such conditions and deserves future clinical evaluation.
8. Perspectives and conclusions While the benefits of cardiovascular events reduction associated with good BP control are undisputable, the control of BP remained disappointingly low despite the advances in pharmacological treatment. Efforts are now diverting in search of alternative solutions to the problem. Non-pharmacological treatments such as carotid baroreceptor stimulation have shown promising results in their preliminary reports, yet their efficacy and safety remained doubtful. On the other hand, transcatheter renal denervation offers a safe and effective therapeutic option in the treatment of resistance hypertension. However, many questions remained to be answered regarding this technique, such as the long term safety data, and the absolute benefits on cardiovascular mortality. Cost-effectiveness is another concern, although one might argue that a one-off cost might actually off-set the cost of life-long medication. Future research should be directed in a larger and more diverse group of patient to better investigate the safety and the efficacy of this technique, and to identify the predictors that will indicate who will respond most to this novel technique. Investigations should also be conducted to explore other possibilities of this technique, such as the feasibility of it being an alternative to pharmacological treatments in patients with milder form of hypertension, and its application in other condition associated with excessive sympathetic activity such as in diabetes mellitus, obstructive sleep apnea, refractory ascites in chronic liver cirrhosis and congestive heart failure. The freedom from the inconvenience, the financial costs and the side-effects of life-long anti-hypertensive treatment attract attentions to a permanent therapy for hypertension. With growing evidence and experience in the use of transcatheter renal denervation, this technique may be the ‘simple’ solution to a chronic and difficult-to-treat medical condition.
Contributors All authors contributed to the development, writing and editing of the article, and all approved the submitted manuscript.
7. Sympathetic inhibition in other conditions
Acknowledgements
Sympathetic overactivation was also observed in several other conditions such as chronic heart failure and hepatic cirrhosis with portal hypertension. It was observed that the plasma concentration
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1-2).
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
G.-M. Tam et al. / International Journal of Cardiology xxx (2012) xxx–xxx
Reference [1] Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–23. [2] Whitworth JA. World Health Organization, International Society of Hypertension Writing Group, 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21:1983–92. [3] Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51:1403–19. [4] Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 2011;57:1076–80. [5] Anderson EA, Sinkey CA, Lawton WJ. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension 1989;14:177–83. [6] Schlaich MP, Kaye DM, Lambert E. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 2003;108:560–5. [7] Julius S, Gudbrandsson T, Jamerson K. The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension. Blood Press 1992;1:9–19. [8] Barajas L, Liu L, Powers K. Anatomy of the renal innervation: intrarenal aspects and ganglia of origin. Can J Physiol Pharmacol 1992;70:735–49. [9] DiBona GF. Neural control of the kidney: past, present, and future. Hypertension 2003;41:621–4. [10] DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 1997;77:76–197. [11] Kopp U, Aurell M, Sjölander M, et al. The role of prostaglandins in the alpha- and beta- adrenoceptor-mediated renin release response to graded renal nerve stimulation. Pfluegers Arch 1981;391:1–8. [12] Stella A, Zanchetti A. Functional role of renal afferents. Physiol Rev 1991;71:659–82. [13] Hausberg M, Kosch M, Harmelink P. Sympathetic nerve activity in end-stage renal disease. Circulation 2002;106:1974–9. [14] Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. JAMA 1953;152:1501–4. [15] Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81. [16] Rippy MK, Zarins D, Barman NC. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol 2011;100: 1095–101.
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[17] Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911–7. [18] Bakris GL, Williams M, Dworkin L. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36:646–61. [19] Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 2010;376:1903–9. [20] Mahfoud F, Schlaich M, Kindermann I. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011;123:1940–6. [21] Witkowski A, Prejbisz A, Florczak E. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559–65. [22] Ng MM, Sica DA, Frishman WH. Rheos: an implantable carotid sinus stimulation device for the nonpharmacologic treatment of resistant hypertension. Cardiol Rev 2011;19:52–7. [23] Scheffers IJ, Kroon AA, Schmidli J. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–8. [24] Bisognano JD, Bakris G, Nadim MK. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension results from the double-blind, randomized, placebo-controlled Rheos pivotal trial. J Am Coll Cardiol 2011;58: 765–73. [25] Patel NK, Javed S, Khan S. Deep brain stimulation relieves refractory hypertension. Neurology 2011;76:405–7. [26] Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311: 819–23. [27] Esler M, Dudley F, Jennings G. Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis. Ann Intern Med 1992;116: 446–55. [28] Lebrec D, Poynard T, Hillon P, Benhamou J-P. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med 1981;305:1371–4. [29] Foody JM, Farrell MH, Krumholz HM. Beta-Blocker therapy in heart failure: scientific review. JAMA 2002;287:883–9.
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited Guang-Ming Tam a, Bryan P. Yan a, Sharad V. Shetty b, Yat-Yin Lam a,⁎ a b
Prince of Wales Hospital, Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong Royal Perth Hospital, Australia
a r t i c l e
i n f o
Article history: Received 21 December 2011 Accepted 22 January 2012 Available online xxxx Keywords: Transcatheter renal denervation Resistant hypertension Sympathetic nervous system
a b s t r a c t Resistant hypertension, defined as the failure to achieve target blood pressure despite concurrent use of 3 antihypertensive agents of different classes, is estimated to affect 20–30% of hypertensive patients. These patients are vulnerable to cardiovascular, cerebrovascular and renal complications. There is ample evidence that sympathetic nervous system hyperactivity contributes to the initiation, maintenance and progression of hypertension. The renal sympathetic nervous system, in particular, has been identified as a major culprit for the development and progression of hypertension, heart failure and chronic kidney disease in both preclinical and human studies. Traditional surgical sympathectomy proposed in 1940s was halted due to unacceptable operative risk and the emergence of anti-hypertensive medications. Recently, catheter-based renal sympathetic denervation by radiofrequency ablation has shown encouraging intermediate-term results with minimal complications in patients with resistant hypertension. This review summarizes the patho-physiological role of the renal sympathetic nervous system and the potential application of renal denervation therapy for the treatment of resistant hypertension. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hypertension is a common health problem that affects millions of people in the world [1,2]. Poorly controlled blood pressure (BP) leads to cardiovascular, cerebrovascular and renal complications. Despite the availability of multitudes of anti-hypertensive drugs, the percentage of patients achieving optimal control of hypertension has remained disappointingly low [1,2]. Resistant hypertension is defined as the failure to achieve target BP despite concurrent use of 3 antihypertensive drugs of different classes, with one of them being diuretics [3]. The reported prevalence of this condition ranged from 5 to 30% [4]. There are many factors contributing to resistant hypertension such as poor medication adherence, inappropriate drug combination, inadequate dosing, or the presence of secondary causes for hypertension in particular primary hyperaldosteronism, obstructive sleep apnea and chronic kidney disease. However, such factors are not found in the majority of resistant hypertension patients who have activated sympathetic nervous system (SNS) and increased sympathetic outflow. Lifestyle modification, enhancing drug compliance, treating of secondary causes or adding mineralocorticoid receptor antagonist such
⁎ Corresponding author at: Division of Cardiology, SH Ho Cardiovascular and Stroke Centre, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong. Tel.: + 852 26321299; fax: + 852 26373852. E-mail address: [email protected] (Y.-Y. Lam).
as spironolactone or eplerenone are well established strategies to treat resistant hypertension. Recently, catheter-based renal sympathetic denervation by radiofrequency ablation has shown encouraging results with minimal complications in patients with resistant hypertension. This procedure is a safer version of radical surgical sympathectomy which was proposed in the 40s and 50s when therapeutic options for hypertension were limited. This review summarizes the patho-physiological role of the renal SNS and the potential application of renal denervation therapy for the treatment of resistant hypertension and other diseases such as heart failure and chronic kidney disease. 2. Sympathetic nervous systems in hypertension Sympathetic innervations are responsible in the homeostasis mechanism of multiple systems, and overactivities of the SNS have many detrimental effects on various conditions (Fig. 1). In patients with hypertension, there are evidences of sympathetic overactivities as measured by the norepinepherine spill over and increased nerve firing rates in postganglionic sympathetic fibres in skeletal muscle [5]. The increase sympathetic activities contribute to the development of hypertension through the regulatory mechanism on rennin release, alternation of glomerular filtration rate, sodium retention and on cardiac pumping. In addition, SNS overactivities in hypertension have other possible adverse consequences. In the heart, SNS overactivities can cause arrhythmia, and its trophic effect contributes to the development of left ventricular hypertrophy [6]. In the liver, it
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.01.048
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
2
G.-M. Tam et al. / International Journal of Cardiology xxx (2012) xxx–xxx Systemic SNS activation.
Increase cardiac output, arrthymia, left ventricular hypertrophy.
hyperlipidaemia
vasopressin and oxytocin release Insulin resistance, impaired glucose metabolism.
Efferent sympathetic activations.
Increase sodium pump activity.
Afferent sympathetic activations
Increase vascular pressure renal ischemia renal artery occlusion
Renin secreting juxtaglomerular cells Preglomerular vasoconstriction
Fig. 1. Renal sympathetic innervation and relationship to systemic sympathetic system. SNS = sympathetic nervous system.
causes hyperlipidaemia by retarding postprandial clearing of lipids, and causes insulin resistance and hyperinsulinemia by impairing glucose delivery to muscle [7].
ureteropelvic pressure. The chemoreceptors are activated by concentrated substrates and respond to renal ischemia or renal artery occlusion (Fig. 1) [12].
3. Renal sympathetic innervations
4. Renal sympathetic denervation
3.1. Efferent system
It has been long postulated that systemic sympathetic nervous activation plays an important role in the perpetuation of hypertension, and previous human clinical work has shown that nephrectomy in end-stage renal failure patients resulted in reduction of muscle sympathetic nerve activity and calf vascular resistance [13]. Historically, non-selective surgical sympathectomy, often called ‘splanchnicectomy’ as it involved abdominal organs, was performed in patients with severe or malignant hypertension in the era where effective antihypertensive therapy was lacking. In these patients, surgery reduced sympathetic outflow to the kidneys, increased natriuresis and diuresis, and decreased renin release, without adversely affecting other functions of the kidney. While effective in reducing BP and improving survival, splanchnicectomy is a major surgery requiring a specialized expertise, prolonged hospital stay and has many adverse effects such as orthostatic hypotension, orthostatic tachycardia, palpitation, breathlessness, anhidrosis, cold hands, intestinal disturbance, and erectile dysfunction. These adverse effects can be attributed to the non-specific sympathetic denervation of the viscera and the vasculature of the peripherals [14]. Building on the concept of surgical sympathectomy to control hypertension, a novel catheter-based endovascular renal artery sympathetic denervation has been developed in recent years.
The efferent sympathetic fibers of renal sympathetic nervous system originate from the thoracic and lumbar sympathetic trunk. From there, they reach the T13-L1 ipsilateral and contralateral paravertebral ganglia and the prevertebral superior mesenteric and celiac ganglia. The postganglionic nerve fibers then run alongside the renal artery and enter the hilus of the kidneys, and from there they divide into smaller bundles and penetrate the cortical and juxtamedullary area alongside small blood vessels [8]. The activation of these sympathetic fibers has several effects. Firstly, the release of norepinephrine from renal sympathetic nerve terminals stimulates the postsynaptic alpha-1 adrenoceptors located on the basolateral membrane of renal tubular epithelial cells and results in an increase in activity of the sodium pump, which increases transepithelial sodium transport. Secondly, the direct activation of beta-1 adrenoceptors on juxtaglomerular granular cells releases renin and causes antinatriuresis. Finally, renal sympathetic activation produces preferential preglomerular vascular smooth muscle cells contraction and decreases renal blood flow and glomerular filtration rate (Fig. 1) [9–11]. 3.2. Afferent system
5. Transcatheter renal denervation (Table 1) Renal afferent nerves start from the renal pelvic wall, exit along the renal artery and extend to ipsilateral dorsal root ganglia. Their activation contributes directly to systemic hypertension by modulating central sympathetic nervous system activity and promoting vasopressin and oxytocin release from the neuro-hypophysis. There are 2 types of afferent receptors in the renal pelvis. The mechanoreceptors respond to increases in renal arterial or venous pressures or
This technique utilizes a radiofrequency ablation catheter (Symplicity® by Medtronic Inc., Minneapolis, MN, USA) which is introduced into each renal artery via femoral arterial access. Up to 6 discrete low-power radiofrequency ablations of 8 Watts or less lasting up to 2 min each is applied separated both longitudinally and rotationally within each renal artery (Fig. 2). The aim of ablation is
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
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Fig. 2. The Symplicity® catheter is a 5 French catheter specifically designed for renal sympathetic denervation. It is inserted through femoral artery and is positioned at the lumen of the renal artery. The catheter is then connected to a proprietary radiofrequency generator with built-in safety algorithms for delivering the therapy (a). Selective renal arteriogram is performed before the procedure with the aid of a dedicated guiding catheter (b). A total of 4 to 6 radiofrequency ablations would be delivered in an interrupted, spiral fashion within the renal artery (c). The arrow indicates the tip of the denervation catheter.
to disrupt the renal nerves located at the adventitia of these arteries which has been shown to effectively reduce renal norepinepherine spillover [15]. Optimal site for ablation is determined by contact impedance between the catheter tip and vessel wall. During ablation, tip temperature and impedance is monitored by the catheter system altering radiofrequency energy delivery in response to a predetermined algorithm. Adequate ablation is determined by significant drop in contact impedance after each ablation. There is no objective measure of procedural success at the time of procedure because the therapeutic effect of renal denervation in BP lowering is delayed up to 3 months (Table 1). This new technique has several advantages over the traditional surgical sympathectomy. Firstly, it is minimally invasive, and has a short procedural and recovery time. Secondly, it is selective and specific, hence avoiding the systemic adverse effects of surgical sympathectomy. Thirdly, as endovascular procedure and radiofrequency ablation are routinely practiced by interventional radiologists and cardiologists, this new catheter-based procedure can be assumed to be widely adaptable. Preclinical studies of this catheter-based procedure by Medtronic Inc. in juvenile swine reported comparable reduction in sympathetic activity to direct surgical sympathectomy, and the catheter-based procedure resulted in no renal arterial stenosis or thrombosis, nor gross or microscopic abnormalities in the kidney, surrounding stroma, or urinary bladder 6 months post procedure. Microscopically, only fibrosis of 10–25% of the total media and underlying adventitia, with mild disruption of the external elastic lamina was observed in the renal artery, with no significant smooth muscle hyperplasia or inflammatory components noted [16]. The first human study of catheter-based renal denervation was published as a proof-of-principle cohort study by Krum H. et al. This study aimed to assess the safety and the effectiveness of renal denervation in 45 patients with resistance hypertension and suitable renal arterial anatomy. In this study, renal denervation resulted in a significant and sustained BP reduction at one year [15]. Subsequent longerterm follow-up data of the studied cohort demonstrated durability of
BP reduction of up to 24 months [17]. In 10 of the patients, renal norepinepherine spillover was also measured after the procedure and was shown to be reduced by 47%. Peri-procedural and long-term safety was another endpoint being assessed in this study. Peri-procedural complication was observed in 2 cases in this study population, and 2 others in the later-published longer-term report. With the exception of 1 renal artery dissection occurring before the procedure, all of these complications were related to pseudoaneurysm or hematoma formation at the femoral arterial puncture sites. There was no renovascular complication occurring immediately after the procedure on renal angiographic studies and at 6 months of follow-up scans. There was a gradual decline in estimated glomerular filtration rate (eGFR) at 6 months (− 1.6 ML/min) and at 24 months of follow-up (−16.0 ML/min). However, the rate of decline is less than would be predicted based on natural history studies [18], and some of these patients had spironolactone or other diuretics added after the procedure, which might contributed to the decline in eGFR. In any case, eGFR data were only available in 10 patients at 24 months, and thus were not representative. The major limitation of this study is that it has no control group with which to make comparison regarding BP response and eGFR changes to. The term ‘resistant hypertension’ in this study was loosely defined and lacked proper investigation such as ruling out white-coat syndrome, or secondary hyperaldosteronism. Nevertheless this proof-of-principle study and its subsequent longer-term follow-up report have provided preliminary evidence that catheter-based renal denervation is a safe and effective technique with durable BP lowering effect. These data paved the way for the subsequent randomized controlled trial – the Symplicity HTN-2 Trial. The Symplicity HTN-2 Trial was conducted in a larger population of 106 patients, using the same inclusion criteria as in the pioneer study. These 106 patients were randomized into renal denervation group or to control group (maintenance of previous medical treatment alone). At 6 months, there was a significant reduction of office based BP by 33/11 mmHg when comparing with the control group.
Table 1 Completed clinical studies [14,19–21] on transcatheter renal denervation therapy. Author/trial acronyms
Sample size
Mean change in BP at 6 months (systolic/diastolic)
Important findings
Krum et al. Symplicity HTN-2
45 106
− 22/−11 mmHg − 32/−12 mmHg
Mahfoud et al.
50
− 32/−12 mmHg*
Witkowski et al.
10
− 34/−13 mmHg
Renal denervation produces significant BP reduction without serious adverse events. Renal denervation is safe and effective in producing substantial BP reduction as compared to medical treatment alone In addition to BP reduction, renal denervation also improves glucose metabolism and insulin sensitivity. In addition to BP reduction, renal denervation also improves glycemic control and reduces sleep apnea severity.
*3-month results. BP = blood pressure.
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
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The reduction of BP was still significant after taking into account the effects of medication adjustment and on 24 h ambulatory BP monitoring. There were 5 hospital admissions for hypertensive emergency during the study period: 3 in the renal denervation group and 2 in the treatment group. The authors also reported 5 serious adverse events in both the renal denervation (1 transient ischemic attack and 1 angina requiring a coronary stent) and control (2 transient ischemic attacks and 1 angina requiring stenting) groups. There was no serious complication related to the procedure. There was no significant difference in the decline of eGFR or reno-vascular complications either between the 2 groups [19]. While confirming the findings in the pioneer study, this randomized trials shared the same limitations of having a relatively small sample size and a short follow-up period for the assessment of composite cardiovascular events. To address these issues, the Symplicity HTN-3 trial which is a multi-center, larger-scaled, randomized, controlled study including a sham procedure in the control group is currently underway. Similar to the first study, the Symplicity HTN-2 Trial did not clearly define the ‘resistant hypertension’ either, and did not exclude the possibilities such as secondary hypertension. Moreover, the baseline characteristics of patients were different between the 2 groups, with the renal denervation group having more males (65% vs. 50%), higher rates of diabetes (40% vs. 28%) and higher prevalence of coronary artery disease (19% vs. 7%). These differences might indicate more serious cases of hypertension in the renal denervation group and skewed the result in favor of the control group. In spite of these limitations, this trial adds strong evidence supporting the effectiveness and safety of catheter-based renal denervation [19]. In addition to significant BP reduction, renal denervation was also shown to be effective in the treatment of other conditions coexisting with resistant hypertension. In a small study, renal denervation was shown to improve glucose metabolism by reducing the fasting glucose level and insulin sensitivity by decreasing insulin level and Cpeptide level, on top of a significantly reducing BP [20]. Another non-randomized, open-label study even demonstrated an improvement of sleep apnea severity in patients treated with renal denervation, as well as BP reduction and blood glucose control [21]. 6. Other minimally-invasive approaches for Sympathetic Inhibition Other minimally invasive treatments of hypertension aiming at sympathetic nervous system inhibition have also received attention recently. Among them is the carotid baroreceptor activation therapy. The concept was based on the assumption that the continuous carotid nerve stimulation causes sympathetic inhibition as the body senses a constant rise in blood pressure, and this subsequent will result in BP reduction. This approach involves implanting an external pulse generator, the Rheos device, which connects to 2 electrodes leads that are placed at the perivascular space of carotid sinus [22]. While showing promising results in animal models as well as in the early feasibility study [23], this approach failed to achieve satisfactory BP control or safety end points in the recent published randomized controlled trial [24]. Another potential approach is the deep brain stimulation which stimulates ventrolateral periaqueductal gray and periventricular gray areas and evokes hypotension associated with peripheral vasodilatation indicating a sympathetic inhibition. The original intend of this approach is for pain relief, but it was also demonstrated to have hypotensive effect in a subject with refractory hypertension [25].
of norepinepherine was increased in patient with heart failure, and that the prognosis of patient with heart failure was related to plasma concentration of norepinepherine [26]. In patients with hepatic cirrhosis and portal hypertension, it has been shown that the norepinephrine spillover to plasma was higher from the hepatomesenteric circulation and from the renal circulation [27]. These sympathetic overactivities will probably promote sodium retention, increase the post-sinusoidal resistance and perpetuate portal venous hypertension. The benefits of sympathetic inhibition have been long established in the 2 aforementioned conditions. In portal hypertension, administer of clonidine has shown to reduced the post-sinusoidal vascular resistance [27] and use of beta-blocker has been shown to prevent variceal bleeding and refractory ascites [28]. In patients with heart failure, the beneficial effects of sympathetic inhibitions are even more robust. Numerous studies have shown that the use betablocking agents provide survival advantages in patient with heart failure [29]. Minimally-invasive sympathetic inhibition such as renal denervation therefore might be beneficial in patients with such conditions and deserves future clinical evaluation.
8. Perspectives and conclusions While the benefits of cardiovascular events reduction associated with good BP control are undisputable, the control of BP remained disappointingly low despite the advances in pharmacological treatment. Efforts are now diverting in search of alternative solutions to the problem. Non-pharmacological treatments such as carotid baroreceptor stimulation have shown promising results in their preliminary reports, yet their efficacy and safety remained doubtful. On the other hand, transcatheter renal denervation offers a safe and effective therapeutic option in the treatment of resistance hypertension. However, many questions remained to be answered regarding this technique, such as the long term safety data, and the absolute benefits on cardiovascular mortality. Cost-effectiveness is another concern, although one might argue that a one-off cost might actually off-set the cost of life-long medication. Future research should be directed in a larger and more diverse group of patient to better investigate the safety and the efficacy of this technique, and to identify the predictors that will indicate who will respond most to this novel technique. Investigations should also be conducted to explore other possibilities of this technique, such as the feasibility of it being an alternative to pharmacological treatments in patients with milder form of hypertension, and its application in other condition associated with excessive sympathetic activity such as in diabetes mellitus, obstructive sleep apnea, refractory ascites in chronic liver cirrhosis and congestive heart failure. The freedom from the inconvenience, the financial costs and the side-effects of life-long anti-hypertensive treatment attract attentions to a permanent therapy for hypertension. With growing evidence and experience in the use of transcatheter renal denervation, this technique may be the ‘simple’ solution to a chronic and difficult-to-treat medical condition.
Contributors All authors contributed to the development, writing and editing of the article, and all approved the submitted manuscript.
7. Sympathetic inhibition in other conditions
Acknowledgements
Sympathetic overactivation was also observed in several other conditions such as chronic heart failure and hepatic cirrhosis with portal hypertension. It was observed that the plasma concentration
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1-2).
Please cite this article as: Tam G-M, et al, Transcatheter renal artery sympathetic denervation for resistant hypertension: an old paradigm revisited, Int J Cardiol (2012), doi:10.1016/j.ijcard.2012.01.048
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Reference [1] Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–23. [2] Whitworth JA. World Health Organization, International Society of Hypertension Writing Group, 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21:1983–92. [3] Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008;51:1403–19. [4] Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 2011;57:1076–80. [5] Anderson EA, Sinkey CA, Lawton WJ. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension 1989;14:177–83. [6] Schlaich MP, Kaye DM, Lambert E. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 2003;108:560–5. [7] Julius S, Gudbrandsson T, Jamerson K. The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension. Blood Press 1992;1:9–19. [8] Barajas L, Liu L, Powers K. Anatomy of the renal innervation: intrarenal aspects and ganglia of origin. Can J Physiol Pharmacol 1992;70:735–49. [9] DiBona GF. Neural control of the kidney: past, present, and future. Hypertension 2003;41:621–4. [10] DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 1997;77:76–197. [11] Kopp U, Aurell M, Sjölander M, et al. The role of prostaglandins in the alpha- and beta- adrenoceptor-mediated renin release response to graded renal nerve stimulation. Pfluegers Arch 1981;391:1–8. [12] Stella A, Zanchetti A. Functional role of renal afferents. Physiol Rev 1991;71:659–82. [13] Hausberg M, Kosch M, Harmelink P. Sympathetic nerve activity in end-stage renal disease. Circulation 2002;106:1974–9. [14] Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. JAMA 1953;152:1501–4. [15] Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275–81. [16] Rippy MK, Zarins D, Barman NC. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol 2011;100: 1095–101.
5
[17] Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911–7. [18] Bakris GL, Williams M, Dworkin L. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36:646–61. [19] Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 2010;376:1903–9. [20] Mahfoud F, Schlaich M, Kindermann I. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011;123:1940–6. [21] Witkowski A, Prejbisz A, Florczak E. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559–65. [22] Ng MM, Sica DA, Frishman WH. Rheos: an implantable carotid sinus stimulation device for the nonpharmacologic treatment of resistant hypertension. Cardiol Rev 2011;19:52–7. [23] Scheffers IJ, Kroon AA, Schmidli J. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–8. [24] Bisognano JD, Bakris G, Nadim MK. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension results from the double-blind, randomized, placebo-controlled Rheos pivotal trial. J Am Coll Cardiol 2011;58: 765–73. [25] Patel NK, Javed S, Khan S. Deep brain stimulation relieves refractory hypertension. Neurology 2011;76:405–7. [26] Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311: 819–23. [27] Esler M, Dudley F, Jennings G. Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis. Ann Intern Med 1992;116: 446–55. [28] Lebrec D, Poynard T, Hillon P, Benhamou J-P. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med 1981;305:1371–4. [29] Foody JM, Farrell MH, Krumholz HM. Beta-Blocker therapy in heart failure: scientific review. JAMA 2002;287:883–9.
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