Samir Rafla- Renal denervation

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Catheter-Based Renal Sympathetic Denervation in the Management of Resistant Hypertension

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Catheter-Based Renal Sympathetic Denervation in the Management of Resistant Hypertension :

Catheter-Based Renal Sympathetic Denervation in the Management of Resistant Hypertension Prof. Samir Morcos Rafla Alexandria Univ. 1

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The Renal Sympathetic Nervous System

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The European Society of Cardiology (ESC) has issued a consensus statement regarding the use of catheter-based renal denervation for the treatment of high blood pressure, stating that the novel therapy can be considered a therapeutic option in patients with drug-resistant hypertension who cannot get to goal with a combination of lifestyle and pharmacologic therapy.

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6 The data support the concept that the radiofrequency ablation of the renal nerves reduces blood pressure and improves blood-pressure control in these difficult-to-treat patients. The data supporting the treatment now extend to 36 months Mahfoud F, et al. Expert consensus document from the European Society of Cardiology on catheter-based renal denervation. Eur Heart J 2013; DOI:10.1093

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7 Patients are eligible for renal denervation if they meet the following criteria: Office-based blood pressure > 160 mm Hg ( > 150 mm Hg in patients with type diabetes). Use of three or more antihypertensive drugs in adequate dosage and combination, including use of a diuretic. Have attempted to modify blood pressure with lifestyle changes. Secondary hypertension has been excluded. Pseudoresistance has been excluded with the use of ambulatory blood-pressure monitoring. Patients have preserved renal function (glomerular filtration rate > 45 mL/min/1.73 2 ). Absence of polar or accessory arteries, no renal artery stenosis, and no prior renal revascularization.

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8 The ESC consensus statement acknowledges that it is not yet clear how renal denervation works, but the mechanism is likely the result of a reduction in peripheral resistance, reduced renin release, and favorable changes in water and salt handling. "The fact that renal denervation also reduces whole-body sympathetic-nerve activity suggests that this therapy may also be beneficial in other clinical states characterized by sympathetic nervous system activation—this may ultimately lead to new indications,"

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SYMPLICITY HTN-2 (Renal Denervation in Patients With Uncontrolled Hypertension):

SYMPLICITY HTN-2 (Renal Denervation in Patients With Uncontrolled Hypertension) Background: Renal sympathetic efferent and afferent nerves are crucial for the initiation and maintenance of systemic hypertension Denervation of the renal sympathetic nerve to reduce BP has been attempted, unsuccessfully, by surgical means years ago Population and treatment: 106 patients with resistant hypertension (SBP >160 mm Hg, or >150 mm Hg for those with type 2 diabetes, taking ≥ three antihypertensive drugs) Randomized 1:1 to renal denervation + previous treatment (n=52) or previous treatment alone (n=51) Primary outcome: BP reduction at six months MD Esler (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) American Heart Association 2010 Scientific Sessions

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Average office-based BP in the renal-denervation group was reduced 32/12 mm Hg (average baseline 178/96 mm Hg) six months after the ablation Between-group differences in BP at six months were 33/11 mm Hg (p<0.0001) Of the patients in the ablation arm, 84% had a 10-mm-Hg or greater drop in SBP vs 35% of controls (p<0.0001) There did not appear to be any adverse events: Imaging of renal arteries for damage showed no evidence of renal artery stenosis or aneurysmal dilatation during the six-month follow-up There were no changes in renal function, even in those with mild to moderate renal failure SYMPLICITY HTN-2: Results

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SYMPLICITY HTN-2: Commentary* *All comments from A revolutionary road for resistant hypertension? Renal denervation in Symplicity HTN-2 (http://www.theheart.org/article/1151787.do) "This has the potential for really revolutionizing the way we treat resistant hypertension, which is an enormous clinical need." - Dr Suzanne Oparil "I've never seen BP falls as big as this from any other treatment process, which makes the possibility of cure realistic; it might be within reach." - Dr Murray D Esler "My only reservation about the study is that they have not compared the denervation with the most effective add-on drug in patients with resistant hypertension, which is spironolactone." - Dr Peter Sever

Anatomical Location of Renal Sympathetic Nerves :

Anatomical Location of Renal Sympathetic Nerves Arise from T10-L1 Follow the renal artery to the kidney Primarily lie within the adventitia

Anatomical Location of Renal Sympathetic Nerves :

Anatomical Location of Renal Sympathetic Nerves Arise from T10-L1 Follow the renal artery to the kidney Primarily lie within the adventitia Vessel Lumen Media Adventitia Renal Nerves

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RF Ablation Approach to Renal Sympathetic Denervation Electrode Insulated arch wire Symplicity ® Catheter System, Ardian, Inc., Palo Alto, CA, USA

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Placement of Renal RF Catheter

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Treatment by Renal RF Catheter

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Treatment by Renal RF Catheter

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Treatment by Renal RF Catheter

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Treatment by Renal RF Catheter

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Treatment involves approximately 4 to 6 applications Using low-power (8 W) radiofrequency energy. Treatments are delivered in a helical fashion within the renal artery by rotation of the catheter and approximately 5 mm pullback between ablations. The generator provides the radiofrequency energy according to an automated algorithm

Hypertension Epidemiology:

Hypertension Epidemiology Single largest contributor to death worldwide Every 20/10 mmHg increase in BP correlates with a doubling of 10-year cardiovascular mortality Dramatically increases risk of stroke, heart attack, heart failure, & kidney failure Only half of all treated hypertensives are controlled to established BP targets High prevalence: Affects 1 in 3 adults 1B people worldwide  1.6 B by 2025 35% Treated & Controlled 30% Untreated 35% Treated but Uncontrolled Chobanian et al. Hypertension.  2003;42(6):1206–1252. 23 c

Renal Sympathetic Activation: Efferent Nerves Kidney as Recipient of Sympathetic Signals:

Renal Sympathetic Activation: Efferent Nerves Kidney as Recipient of Sympathetic Signals Renal Efferent Nerves ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 24

Renal Sympathetic Activation: Afferent Nerves Kidney as Origin of Central Sympathetic Drive:

Hypertrophy Arrhythmia Oxygen Consumption Vasoconstriction Atherosclerosis Insulin Resistance Renal Sympathetic Activation: Afferent Nerves Kidney as Origin of Central Sympathetic Drive Renal Afferent Nerves ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow Sleep Disturbances 25

Renal Nerve Anatomy :

Nerves arise from T10-L2 The nerves arborize around the artery and primarily lie within the adventitia Renal Nerve Anatomy Vessel Lumen Media Adventitia Renal Nerves 26 26

Renal Nerve Anatomy Allows a Catheter-Based Approach:

Renal Nerve Anatomy Allows a Catheter-Based Approach 27 Renal artery access via standard interventional technique 4-6 two-minute treatments per artery Proprietary RF generator Automated Low power Built-in safety algorithms Spacing of e.g. 5 mm.

Baseline Patient Characteristics (n=153):

Baseline Patient Characteristics (n=153) 29 Symplicity HTN-1 Investigators. Hypertension . 2011;57:911-917. Demographics Age (years) 57 ± 11 Gender (% female) 39% Race (% non-Caucasian) 5% Co-morbidities Diabetes Mellitus II (%) 31% CAD (%) 22% Hyperlipidemia (%) 68% eGFR (mL/min/1.73m 2 ) 83 ± 20 Blood Pressure Baseline BP (mmHg) 176/98 ± 17/15 Number of anti-HTN meds (mean) 5.1 ± 1.4 Diuretic (%) 95% Aldosterone blocker(%) 22% ACE/ARB (%) 91% Direct Renin Inhibitor 14% Beta-blocker (%) 82% Calcium channel blocker (%) 75% Centrally acting sympatholytic (%) 33% Vasodilator (%) 19% Alpha-1 blocker 19%

Brief Procedure with a Low Complication rate (n=153):

Brief Procedure with a Low Complication rate (n=153) 38 minute median procedure time Average of 4 ablations per artery Intravenous narcotics & sedatives used to manage pain during delivery of RF energy No catheter or generator malfunctions No major complications Minor complications 4/153: 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae 3 access site complications , treated without further sequelae 30 Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Symplicity HTN-1: BP Reductions through 3 years:

Symplicity HTN-1: BP Reductions through 3 years BP change (mmHg) P<0.01 for ∆ from BL for all time points *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

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Therapeutic renal sympathetic denervation involves a brief, simple percutaneous procedure No major complications were observed to either the renal artery or the kidney Significant and sustained reductions in blood pressure were achieved in patients with resistant hypertension Achievement of denervation supported by significant reduction in renal norepinephrine spillover Summary

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Conclusions Renal denervation offers a novel and safe catheter-based approach for selective reduction of renal sympathetic drive. We demonstrated for the first time that selective denervation of the renal sympathetic nerves has the potential to improve glucose metabolism and blood pressure control concurrently in patients with resistant hypertension in the absence of significant changes in body weight and alterations in lifestyle or antihypertensive medication.

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J Clin Hypertens . 2012;14:799–801. 2012 The Ohio State University, Columbus, OH;

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35 Attenuation of sympathetic activity may have a multitude of effects beyond those directly related to hypertension. Increased sympathetic nervous system activity, for example, is associated with heightened risk of death among heart failure patients. Further, salt and water retention in some forms of heart failure may be mediated in large part by renal sympathetic activity, and selective renal denervation may play a role in treatment or prevention of heart failure and the cardiorenal syndrome. Recent reports in patients with insulin resistance or type II diabetes mellitus, polycystic ovary syndrome, and hypertension have also suggested improved insulin resistance and glycemic control with denervation therapy.

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Multi-electrode renal-denervation device appears safe:

Multi-electrode renal-denervation device appears safe 38

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39 RD offers a novel and safe catheter-based approach for selective reduction of renal sympathetic drive. We demonstrate for the first time to our knowledge that selective denervation of the renal sympathetic nerves in addition to lowering peripheral BP significantly reduces LV mass and improves diastolic function in patients with resistant hypertension.

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40 Renal denervation has been shown to reduce fasting plasma glucose, fasting plasma insulin, insulin resistance, and haemoglobin A1C levels in diabetic patients with resistant hypertension. In patients with obstructive sleep apnoea and resistant hypertension, renal denervation resulted in improvements in glucose profiles as well as sleep apnoea symptoms. There is some evidence that renal denervation exerts a renoprotective effect in diabetic nephropathy. Excerpta Medica Feb 19, 2013

Hints of renal-denervation side benefit: Fewer ventricular arrhythmias Renal sympathetic denervation significantly reduces mean heart rate and exerts a favorable effect on atrial and ventricular arrhythmias in resistant hypertensives. American College of Cardiology 2013 Scientific Sessions; March 9, 2013; San Francisco, CA. Abstract 1148-22. :

Hints of renal-denervation side benefit: Fewer ventricular arrhythmias Renal sympathetic denervation significantly reduces mean heart rate and exerts a favorable effect on atrial and ventricular arrhythmias in resistant hypertensives. American College of Cardiology 2013 Scientific Sessions; March 9, 2013; San Francisco, CA. Abstract 1148-22 . 41

Renal-artery denervation can help to reduce the recurrence of atrial fibrillation in concert with pulmonary-vein isolation (PVI) in patients with drug-resistant hypertension. 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 Coll Cardiol 2012; 05.036:

Renal-artery denervation can help to reduce the recurrence of atrial fibrillation in concert with pulmonary-vein isolation (PVI) in patients with drug-resistant hypertension. 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 Coll Cardiol 2012; 05.036 42

Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the Simplicity(R) catheter system and the EnligHTN™ multi-electrode renal denervation catheter. Eur Heart J Apr 2013;:

Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the Simplicity(R) catheter system and the EnligHTN™ multi-electrode renal denervation catheter. Eur Heart J Apr 2013; 43 CONCLUSION: Here we show that diffuse renal artery constriction and local tissue damage at the ablation site with oedema and thrombus formation occur after RNA and that OCT (optical coherent tomography) visualizes vascular lesions not apparent on angiography. This suggests that dual antiplatelet therapy may be required during RNA.

Expert Consensus Document From the European Society of Cardiology on Catheter-Based Renal Denervation. Eur Heart J 2013; Apr 25 1. Hypertension is one of the most frequent chronic diseases worldwide. It is estimated that over the next two decades, up to 50% of the adult population will be diagnosed with hypertension.  2. Resistant hypertension, defined as uncontrolled blood pressure that persists despite the use of three or more antihypertensives of different classes, including a diuretic, at maximal or the highest tolerated dose, is present in 5-10% of patients with hypertension.  :

Expert Consensus Document From the European Society of Cardiology on Catheter-Based Renal Denervation. Eur Heart J 2013; Apr 25 1. Hypertension is one of the most frequent chronic diseases worldwide. It is estimated that over the next two decades, up to 50% of the adult population will be diagnosed with hypertension. 2. Resistant hypertension, defined as uncontrolled blood pressure that persists despite the use of three or more antihypertensives of different classes, including a diuretic, at maximal or the highest tolerated dose, is present in 5-10% of patients with hypertension. 44

3. Renal denervation targeting both afferent and efferent nerves has been demonstrated to reduce sympathetic nerve activity, norepinephrine spillover, and blood pressure in patients with resistant hypertension.  5. The renal artery needs to be at least 4 mm in diameter and at least 20 mm in length for successful denervation, and should be free of significant stenosis or calcification.  6. Transient local de-endothelialization, acute cellular swelling, connective tissue coagulation, and thrombus formation have been demonstrated to occur after renal denervation. Use of aspirin for 4 weeks is empirically recommended based on these findings.  :

3. Renal denervation targeting both afferent and efferent nerves has been demonstrated to reduce sympathetic nerve activity, norepinephrine spillover, and blood pressure in patients with resistant hypertension. 5. The renal artery needs to be at least 4 mm in diameter and at least 20 mm in length for successful denervation, and should be free of significant stenosis or calcification. 6. Transient local de-endothelialization, acute cellular swelling, connective tissue coagulation, and thrombus formation have been demonstrated to occur after renal denervation. Use of aspirin for 4 weeks is empirically recommended based on these findings. 45

7. Improvement in blood pressure rarely occurs immediately, and it often takes several weeks to months before a notable blood pressure reduction is evident. Further, a reduction in pill burden has not been demonstrated in the currently completed randomized trials, although consistent reduction in blood pressure has been noted in both randomized and observational studies. :

7. Improvement in blood pressure rarely occurs immediately, and it often takes several weeks to months before a notable blood pressure reduction is evident. Further, a reduction in pill burden has not been demonstrated in the currently completed randomized trials, although consistent reduction in blood pressure has been noted in both randomized and observational studies. 46

8. Renal denervation results in a significant drop in resting, maximum exercise, and recovery blood pressure, whereas heart rate response during exercise and oxygen uptake is well preserved.  9. Renal denervation is currently being evaluated for heart failure and metabolic syndrome, with small studies demonstrating promising results. Further, the therapy has also been demonstrated to reduce the occurrence of atrial fibrillation and ventricular arrhythmias. :

8. Renal denervation results in a significant drop in resting, maximum exercise, and recovery blood pressure, whereas heart rate response during exercise and oxygen uptake is well preserved. 9. Renal denervation is currently being evaluated for heart failure and metabolic syndrome, with small studies demonstrating promising results. Further, the therapy has also been demonstrated to reduce the occurrence of atrial fibrillation and ventricular arrhythmias. 47