The sympathetic nervous system (SNS) is the body’s catabolic signal for a flight or fight response to stress. Signals responding to stress are sent throughout the body and include:
- Increased heart rate
- Pupil dilation
- Increased blood pressure
- Blood vessels constriction
- Lung dilation
- Peristalsis of digestive tract
- Increased kidney secretion
Kidneys are intimately involved in the sympathetic nervous regulation via the efferent and afferent connections between the kidney and the brain. Interestingly similar to hypertension, congestive heart failure (CHF), left ventricular hypertrophy (LVH), obstructive sleep apnea (OSA), and insulin resistance/type 2 diabetes mellitus (DM) have also been associated with an overactive sympathetic drive.1,2,3
Renal denervation (RDN) is a catheter based endovascular procedure that ablates renal nerves to stop the crosstalk between the kidney and brain, resulting in a reduced sympathetic outflow. Primarily studied for hypertension, RDN is now being studied for the treatment of LVH, CHF, insulin resistant/type 2 DM, and OSA.
The Global SYMPLICITY trial will be evaluating the long-term impact of RDN in more than 5000 patients. The purpose of the registry is to document the long-term safety and effectiveness of renal denervation in patient population with hypertension and gather data for other diseases characterized by elevated sympathetic drive, such as diabetes mellitus type 2, heart failure, renal insufficiency. As investigators are beginning to understand the intrinsic role of the sympathetic nervous system and RDN, it will be interesting to learn new diseases that are benefited.
Congestive Heart Failure
Congestive Heart Failure
CHF patients have increased sympathetic drive with a direct correlation to the intensity of CHF. Pilot studies investigating left ventricular hypertrophy on 46 patients with resistant hypertension that underwent RDN showed that along with reduced blood pressure there was significant regression of left ventricular hypertrophy. Furthermore, RDN patients showed improved myocardial relaxation and end-diastolic pressure.4 The study suggested that RDN in patients with resistant hypertension has a potential cardiac remodeling effect.
Symplicity-HF is an on-going phase II randomized clinical trial to evaluate the efficacy and safety of RDN in treatment of congestive heart failure with preserved LV systolic function. Primary endpoints include symptoms of HF, exercise function, LV filling pressure, LV remodeling, left atrial (LA) size, HF biomarker. Secondary endpoints include safety, BP control, endothelial function, change in renal flow, function and change in vascular function. The study is enrolling patients in UK.
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Approximately 50% of resistant hypertension patients are considered to be insulin resistant, increasing the risk for type II diabetes. RDN may reduce the progression from insulin resistance (pre-diabetes) to diabetes.1 A pilot study enrolled 50 patients with resistant hypertension of which 37 patients underwent RDN and the other 13 were the control. Along with blood pressure reductions, patients that underwent RDN showed reduction in fasting glucose levels from 118+34 mg/dl to 108+38. Similarly in association with the reduction of C-peptide levels, insulin levels decreased from 20.8+3 to 9.3+2.5.1
DREAMS (Denervation of the REnal Artery in Metabolic Syndrome) is a phase III clinical trial that is investigating the effect of RDN on changes in insulin resistance, blood pressure control, safety (MACE), and MSNA (muscle sympathetic nerve acitivity) in patients with metabolic syndrome. The study began enrollment on November 2011 and hopes to have the study completed by May 2014.The study is recruiting patients in The Netherlands.
For more information contact:
Willemien L Verloop, MD +31887556167 firstname.lastname@example.org
MichielVoskuil, MD, PhD +31887556167 email@example.com
Obstructive sleep apnea (OSA) is considered an etiologic factor in development of hypertension and is associated with an increased risk of cardiovascular events (stroke, arrhythmia, heart failure, and sudden cardiac death).5 About 80% of resistant hypertension patients have OSA. OSA-mediated increase in sympathetic drive leads to resistant hypertension.5
In 2011 Witkowski et al published a pilot study that evaluated the effect of RDN on 10 patients diagnosed with resistant hypertension and OSA. Significant decreases were also observed in plasma glucose concentration 2 hours after glucose administration (median: 7.0 versus 6.4 mmol/L; P=0.05) and in hemoglobin A1C level (median: 6.1% versus 5.6%; P<0.05) at 6 months, as well as a decrease in apnea-hypopnea index at 6 months after renal denervation (median: 16.3 versus 4.5 events per hour; P=0.059). The study concluded that RDN may improve severity of OSA as well as hypertension.5
Atrial Fibrillation (Arrhythmia)
Atrial Fibrillation (Arrhythmia)
Hypertension is an important risk factor for developing atrial fibrillation (AF); the incidence of AF also increases with left ventricular (LV) hypertrophy, coronary heart disease, and heart failure, all consequences of poorly controlled hypertension.
In a pilot trial, patients with a history of symptomatic paroxysmal or persistent AF refractory to ≥2 antiarrhythmic drugs and drug-resistant hypertension were randomized to pulmonary vein isolation (PVI) only or PVI with RDN. At the end of 12-month follow-up 69% of patients treated with PVI and RDN were AF-free in comparsion to 29% patients treated with PVI-only (P= 0.033).6 This result generated more inquisitiveness in the role of RDN in treatment of arrhythmia associated with HTN.
Renal denervation was investigated in animal models to test the effect of sympathetic inhibition by renal denervation (RDN) on ventricular ischemia/reperfusion-arrhythmias.7 The effect of RDN in 7 animals were compared with 6 sham animals while subjected to 20 minutes of left anterior descending coronary artery (LAD) occlusion followed by reperfusion. RDN reduced the occurrence of ventricular arrhythmias/fibrillation and attenuated the rise in left ventricular end diastolic pressure during left ventricular ischemia without influencing infarct size, changes in ventricular contractility, blood pressure and reperfusion arrhythmias. Therefore, RDN may protect from ventricular arrhythmias during ischemic events.
Two patients with recurrent monomorphic ventricular tachycardia despite extensive antiarrhythmic therapy were treated with RDN. Following RDN, ventricular tachyarrhythmias were significantly reduced in both patients.8 In another case.8 RDN was effective and safely performed in a hemodynamically unstable patient with ventricular storm after ST elevation myocardial infarction and adjunct catheter ablation. RDN may open a new avenue for an adjunctive interventional bailout treatment of such highly challenging and unstable patients.
- Mahofoud, F, MD, Schlaich M, MD, Kindermann, I, MD, et al. Hypertension Effect of Renal Sympathetic Denervationon Glucose Metabolism in Patients with Resistant Hypertension: A pilot Study. Circulation. 2011; 123:1940-1946
- Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. ActaPhysiol Scand. 2003 Mar;177(3):385-90
- Rundqvist B, Elam M, Bergmann-Sverrisdottir Y, Eisenhofer G, Friberg P. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation. 1997 Jan 7;95(1):169-75.
- Brandt MC, Mahfoud F, Reda S, eta al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am CollCardiol2012; 59; 901-909
- Witkowski et al. 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: 559-565
- Pokushalov E, Romanov A, Corbucci G, et al. A Randomized Comparison of Pulmonary Vein Isolation With Versus Without Concomitant Renal Artery Denervation in Patients With Refractory Symptomatic Atrial Fibrillation and Resistant Hypertension. J Am CollCardiol. 2012;60(13):1163-1170.
- Linz D, Wirth K, Ukena C, et al. Renal Denervation Suppresses Ventricular Arrhythmias During Acute Ventricular Ischemia in Pigs. Heart Rhythm. 2013 Jul 11.
- Ukena C, Bauer A, Mahfoud F et.al. Renal sympathetic denervation for treatment of electrical storm: first-in-man experience.Clin Res Cardiol. 2012 Jan;101(1):63-7.
- Hoffmann BA, Steven D, Willems S, Sydow K. Renal Sympathetic Denervation as an Adjunct to Catheter Ablation for the Treatment of Ventricular Electrical Storm in the Setting of Acute Myocardial Infarction. J CardiovascElectrophysiol. 2013 Jun 12.