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Dr.Wright_RenewalofanOldConceptInHypertension_SJMCCardiovascularSymposium

This document summarizes the key points about renal denervation for treatment of resistant hypertension. It discusses: 1) How renal sympathetic nerves connect the kidney to the brain and how stimulating or blocking these nerves can raise or lower blood pressure. 2) How surgical renal denervation was previously used but had high risks, so was abandoned when safer drug therapies emerged. 3) How catheter-based renal denervation uses radiofrequency energy to ablate the renal sympathetic nerves, providing a minimally invasive alternative. 4) Results from the first human trial (Symplicity HTN-1) showing significant and sustained reductions in both systolic and diastolic blood pressure out to 3 years with

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Renewal of An Old Concept in Hypertension: The Kidney-Brain Connection Richard F. Wright, MD, FACC Pacific Heart Institute Santa Monica, California
Richard F. Wright, M.D. Disclosures Speaking Consulting Research Stock Expert Witness Novartis x x St. Jude Medical x x Boston Scientific x Boeringer-Ingelheim x Glaxo Smith Kline x x Takeda x LipoScience x x Medicare/Palmetto x American College of Cardiology x Leading Cardiologists of America x
What Medical Diagnosis Did These Leaders Share?
Severe Hypertension…
Severe Hypertension… 160/90 190/95 160/110
Severe Hypertension… 160/90 190/95 160/110 All three died of stroke…
A Patient With Resistant Hypertension: Franklin Delano Roosevelt
Resistant Hypertension: Franklin Delano Roosevelt Last blood pressure the day he died in 1945: 300/190
Evolution of Antihypertensive Therapy 1940s 1950 1957-1959 1960s 1970s 1980s 1990s 2000’s Direct ACE ARBs Direct renin vasodilators inhibitor inhibitors Thiazide-type Endothelin Peripheral α-blockers blockers* sympatholytics diuretics Ganglion blockers VPIs* Spironolactone Dihydropyridine Veratrum Devices* alkaloids Central α2 CCB’s Sedatives agonists Renal denervation* General anesthesia Calcium channel blockers β-blockers *Not currently approved for clinical use.
Mortality Benefit of Lowering Blood Pressure CV mortality risk (odds ratio) 1.50 MIDAS/NICS/VHAS Actively controlled trials (ratio experimental/control) UKPDS C vs A Odds ratios >1 Placebo-controlled studies indicate higher or trials with an untreated 1.25 INSIGHT relative risk on control group NORDIL CV Mortality Risk HOT L vs H experimental STOP2/ACEIs treatment HOT M vs H 1.00 MRC2 STOP2/CCBs MRC1 SHEP HEP 0.75 STONE RCT70–80 HOPE Syst-Eur CAPPP UKPDS L vs H Syst-China EWPHE 0.50 PART2/SCAT STOP1 ATMH Negative BP 0.25 values indicate tighter BP regulation on control treatment 0 –5 0 5 10 15 20 25 Difference in office Systolic BP (mmHg) (CONTROL treatment BP minus EXPERIMENTAL treatment BP) 10 Adapted from Staessen JA et al. Hypertens Res. 2005;28:385–407.
BP Control Usually Requires Combination Therapy
Resistant Hypertension Diagnostic and Treatment Algorithm Confirm treatment resistance Improve lifestyle BP >140/90 Weight loss; Exercise and Ultra-low sodium diet On 3 meds at good doses, including thiazide-type diuretic; Eliminate BP raising substances: or on 4 or more meds NSAIDS, sympathomimetics (eg. Exclude “pseudoresistance” decongestants), contraceptives, Licorice, Ephedra, Cocaine Taking medications? Check 24 hour ambulatory BP BP=Blood pressure Adapted from: Calhoun DA et al. Circulation 2008;117(25):e516
Resistant Hypertension, continued Diagnostic and Treatment Algorithm Look for Direct Cause of Hypertension Adjust Pharmacologic Treatment Mineralocorticoid blocker Hyperaldosteronism (eg. spironolactone) Sleep apnea Maximize or change diuretic Renal artery stenosis Use even more agents Pheochromocytoma Try “unusual” BP lowering drugs Cushing’s syndrome Aortic coarctation Refer to hypertension specialist Emerging therapies: ? Renal denervation ? Baroreceptor stimulation Adapted from: Calhoun DA et al. Circulation 2008;117(25):e516
Resistant Hypertension, continued Diagnostic and Treatment Algorithm Look for Direct Cause of Hypertension Adjust Pharmacologic Treatment Mineralocorticoid blocker Hyperaldosteronism (eg. spironolactone) Sleep apnea Maximize or change diuretic Renal artery stenosis Use even more agents Pheochromocytoma Try “unusual” BP lowering drugs Cushing’s syndrome Aortic coarctation Refer to hypertension specialist Emerging therapies: ? Renal denervation ? Baroreceptor stimulation Adapted from: Calhoun DA et al. Circulation 2008;117(25):e516
Renal Sympathetic Efferent Activity: Brain-to-Kidney Adregergic receptors
Renal Sympathetic Afferent Activity: Kidney-to-Brain
Renal Denervation: An Old Idea
Renal Denervation: An Old Idea Smithwick subsequently utilized bilateral lumbodorsal sympathectomy and splanchnicectomy for reduction of blood pressure…
Renal Denervation: An Old Idea Smithwick RH. Am J Med. 1948;4:744-759
Renal Denervation: An Old Idea
Renal Denervation: An Old Idea 70-90% death rate at 5 years on “medical therapy”
Renal Denervation: An Old Idea 20% death rate at 5 years with surgical denervation 70% death rate on medical therapy
Surgical Renal Denervation Very effective in lowering blood pressure…
Surgical Renal Denervation Very effective in lowering blood pressure… but – High morbidity and mortality after surgery – Long-term damage: severe hypotension, syncope, ileus, incontinence, erectile dysfunction
Surgical Renal Denervation Very effective in lowering blood pressure… but – High morbidity and mortality after surgery – Long-term damage: severe hypotension, syncope, ileus, incontinence, erectile dysfunction Therefore, abandoned upon the development of tolerable and effective medical therapies after 1957…
Renal Inervation Renal nerves: • Arise from T10 - L1 • Course along the renal pedicle • Follow the renal artery to the kidney • Lie within the artery adventitia
Renal Inervation Renal nerves: • Arise from T10 - L1 • Course along the renal pedicle • Follow the renal artery to the kidney • Lie within the artery adventitia
Renal Nerves Are In The Adventitia
Effect of Renal Nerve Stimulation Efferent stimulation: Sodium and water retention Increased renin release Afferent stimulation: Increases central sympathetic output
Renal Innervation: Effect of Surgical Denervation Efferent nerves (in red) Afferent nerves (in green) Renal parenchyma Renal artery adventitia 2 days after unilateral denervation Non-denervated side Veelken R et al. JASN 2008;19:1371-1378
Afferent Renal Nerves Nerve cell bodies in the dorsal ganglia Fiber endpoints throughout the kidney: Highest density in the renal pelvis – Mechano-receptors: renal pelvis renal arteries renal veins – Chemo-sensors: interstitial oxygen blood flow pH and local chemistry
Renal Artery Sympathetic Denervation Animal Models: • Spontaneously hypertensive (SHR) rat • Stroke Prone SHR (rat) • New Zealand SHR (rat) • Goldblatt 1Kidney, 1C (rat) • Goldblatt 2Kidney, 2C (rat) • Aortic coarctation (dog) • Aortic nerve transection (rat) • DOCA-NaCl (rat, pig) • Angiotensin II infusion (rat, rabbit) • Fat feeding - Obesity (dog) • Renal wrap (rat) DiBona et al. Physiol Rev. 1997;77:175-197
Renal Artery Sympathetic Denervation Animal Models: • Spontaneously hypertensive (SHR) rat • Stroke Prone SHR (rat) • New Zealand SHR (rat) • Goldblatt 1Kidney, 1C (rat) In every model, • Goldblatt 2Kidney, 2C (rat) renal denervation • Aortic coarctation (dog) lowers blood • Aortic nerve transection (rat) pressure • DOCA-NaCl (rat, pig) • Angiotensin II infusion (rat, rabbit) • Fat feeding - Obesity (dog) • Renal wrap (rat) DiBona et al. Physiol Rev. 1997;77:175-197
Renal Artery Sympathetic Effects, Other Animal Observations: Stimulation of renal afferent nerve raises blood pressure in dogs
Renal Sympathetic Denervation Human Observations: • Nephrectomy lowers blood pressure • Renal transplant patients remain hypertensive if failed kidneys are left in place • Reimplantaion of own kidney lowers blood pressure
Renal Artery Electrical Stimulation Increases Blood Pressure in Humans 35 mm Hg high frequency renal artery stimulation pressure, mmHg, after 10 seconds of Change in central systolic arterial 30 p < 0.001 25 Before renal 20 denervation 15 10 After denervation 5 0 1 2 3 4 5 minutes 27 patients with symptomatic AF and refractory hypertension Pokushalov E. J Am Coll Cardiol 2012; 60:1163-70
Renal Nerve Afferent Sympathetic Traffic • None in normal people • High in: – Renal artery stenosis – Heart failure – Metabolic syndrome – Obese – Insulin resistance and diabetics – Hypertension
Catheter-based Renal Denervation
Multiple Discrete “Burns”
Catheter-based Renal Denervation Kidney 4 to 6 lesions per renal artery depending on length of artery; usually, bilateral procedure Aorta
Catheter-based Renal Denervation
Catheter-based Renal Denervation
Renal Artery Histology 6 Months After Ablation Movat’s pentachrome stain , pigs cutting artifact Zone of energy delivery 20X magnification 100X magnification Minimal intimal thickening and minimal IEL injury overlying areas of mild full thickness medial fibrosis (yellow with green [proteoglycan deposition]), and adventitial fibrosis (yellow). No significant inflammatory cells present.
Renal Denervation: Effect on Sympathetic Tone Schlaich M. N Engl J Med. 2009
(Symplicity HTN-1) • First-in-man 12-month evaluation of percutaneous renal sympathetic denervation in patients with “refractory hypertension.“ • No control group. • Inclusion Criteria: – Office systolic BP ≥160 mmHg despite 3+ anti-hypertensive meds (including a diuretic), or confirmed intolerance to medications – FR (MDRD formula) of ≥ 45 mL/min/1.73m2 • Exclusion Criteria: – Secondary cause of hypertension, or Type I diabetes – Current administration of clonidine, moxonidine, or rilmenidine – Renal artery stenosis, stenting or angioplasty; dual renal arteries Lancet 2009 Apr 11;373(9671):1275-81
Patients Undergoing Procedure: n=45 Anatomically Ineligible: n=5 Age (years) 58 ± 9 51 ± 8 Gender (% female) 44 20 Race (%non-Caucasian) 4 0 Diabetes Mellitus(%) 31 40 CAD (%) 22 20 Heart Rate (bpm) 72 ± 11 79 ± 9 eGFR (mL/min/1.73m2) 81 ± 23 95 ± 15 Office BP (mmHg) 177/101 ± 20/15 173/98 ± 8/9 Number of BP meds (mean) 4.7 ± 1.5 4.6 ± 0.5 ACE/ARB (%) 96 80 Beta-blocker (%) 76 100 Calcium channel blocker (%) 69 100 Vasodilator (%) 18 0 Diuretic (%) 96 60
• No evident complication in 43 of 45 patients: – 1 renal artery dissection during renal catheterization (before RF energy) – 1 femoral artery pseudoaneurysm • No long-term vascular complications observed: – 18 patients with follow-up angiograms (14-30 days post-procedure) – 31 with MRA or CTA at 6-months post-procedure • 4.7 ± 1.5 anti-hypertensive drugs at baseline; unchanged at follow-up • 3 patients required reduction of medications after normalization of BP • 9 patients had their medications increased: – 5 were BP responders: >10mmHg BP reduction prior to med increase – 4 were BP non responders Lancet 2009 Apr 11;373(9671):1275-81
Symplicity HTN-1: BP Reductions Through 3 years 0 -5 -10 -9 BP change -10 -10 (mmHg) -12 -15 -13 -14 -15 -20 -19 -19 -21 -22 -25 Systolic BP -26 -26 Diastolic BP -30 -35 -33 -33 -33 P<0.01 for ∆ from BL for all time points 1M 3M 6M 12 M 18 M 24 M 30 M 36 M (n=143) (n=148) (n=144) (n=130) (n=107) (n=59) (n=24) (n=24) *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)
The Symplicity HTN-2 Trial Randomized trial of catheter-based renal denervation • 106 pts randomized 1:1 to renal denervation vs. control • 24 centers in Europe, Australia, & New Zealand (67% were hypertension centers of excellence). • PRIMARY ENDPOINT: Office systolic BP change, 6 months • SECONDARY ENDPOINTS: Safety and procedural issues 6-month: Renovascular & kidney function Composite CV endpoint BP reduction, 24 hour Ambulatory BP monitoring LV function and mass by cardiac MRI Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
The Symplicity HTN-2 Trial • Inclusion Criteria: – Office SBP 160 mmHg ( 150 mmHg if type II diabetic) Actual randomized baseline BP: 178/97 – > 3 anti-hypertensive meds, on stable medical regimen Actual mean number of meds: 5.2 (2/3 on 5 or more) – Age 18-85 years and estimated GFR > 45 mL/min/1.73m2 • Exclusion Criteria: – No significant renal artery abnormalities or prior intervention – Type I diabetes – Contraindication to MRI – MI, unstable angina, or CVA in the prior 6 months – Pregnancy Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
Centers: Symplicity HTN-2 Europe & Australia/NZ Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
The Symplicity HTN-2 Trial: 6-Month Office Blood Pressure Results RDN (n=49) Control (n=51) 10 ∆ from 1 Baseline 0 0 to 6 Months Diastolic Systolic Diastolic -10 (mmHg) -12 -20 -30 Systolic -32 -40 p<0.0001 vs. control -50 • 84% of RDN patients had ≥ 10 mmHg reduction in SBP • 10% of RDN patients had no reduction in SBP Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
The Symplicity HTN-2 Trial: Results Esler M, Lancet, 2011;376:1074-1075
Symplicity HTN-2: Renal Function Results Treated at Randomization Randomized Baseline 6 month 12 months N=47 eGFR (ml/min/1.73m2) 76.9 ±19.3 (n= 49) 77.1±18.8 (n=49) 78.2±17.4 (n=45) Cystatin C (mg/L) 0.91±0.25 (n=38) 0.98±0.36 (n=40) 0.98±0.30 (n=38) Treated after 6-mo follow-up Crossover Baseline 6 month 12 months N=35 eGFR (ml/min/1.73m2) 88.8 ± 20.7 (n = 35) 89.3±19.5 (n = 35) 85.2±18.3 (n = 35) Cystatin C (mg/L) 0.78 ± 0.17 (n=27) 0.82±0.16 (n=26) 0.89±0.20 (n=26)
The Symplicity HTN-2 Trial: Results Mean change in office BP at 6 months: Denervation patients: 32/12 mmHg Control patients: -1/0 mmHg p=0.001 Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
The Symplicity HTN-2 Trial: Results Mean change in office BP at 6 months: Denervation patients: -32/12 mmHg Control patients: -1/0 mmHg p=0.001 24-hour ambulatory BP results: • Renal denervation: -11/-7 mmHg p=0.006 systolic • Control: -3/ -1 mmHg p=0.51 for systolic No change in estimated GFR, serum creatinine, or cystatin C at 6 months Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
The Symplicity HTN-2 Trial: Safety Device or procedure related adverse events (total n=52): 2 minor adverse events: • 1 femoral artery pseudoaneurysm • 1 reduction in BP requiring reduction in BP medication 6-month renal imaging (n=43, 37 Duplex echo, 5 MRI, 5 CT): • No new renal vascular abnormality • Progression of a pre-existing renal artery stenosis in 1 patient (thought unrelated to ablation ) Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
Renal Denervation Reduces Left Ventricular Hypertrophy 16 14 p = 0.007 Baseline 12 1 month 10 6 months 8 Septal thickness, Septal thickness, Septal thickness, mm mm mm 46 patients after renal denervation: BP reduced 27/8.8 mmHg at 6 months Brandt MD. J Am Coll Cardiol 2012; 59:901-909
Renal Denervation Reduces Left Ventricular Hypertrophy 60 55 50 p < 0.0001 Baseline 45 1 month 40 35 6 months 30 LV mass index, LV mass index, LV mass index, g/m2 g/m2 g/m2 46 patients after renal denervation: BP reduced 27/8.8 mmHg at 6 months Brandt MD. J Am Coll Cardiol 2012; 59:901-909
Eligibility for Renal Denervation in Resistant Hypertension: Enthusiasm Meets Reality Diagram showing patient screening for renal denervation in accordance with a European Society of Hypertension position paper. BP = blood pressure; eGFR = estimated glomerular filtration rate; HTN = hypertension. S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
Eligibility for Renal Denervation in Resistant Hypertension: Enthusiasm Meets Reality S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
Eligibility for Renal Denervation in Resistant Hypertension: Enthusiasm Meets Reality S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
Eligibility for Renal Denervation in Resistant Hypertension: Enthusiasm Meets Reality 1,209 potential patients became 15 “eligible” patients… S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
Renal Artery Stenosis After Ablation B. Kaltenbach, J Am Coll Cardiol. 2012;60(25):2694-2695
Renal Denervation: Utility in Disease States Other Than Hypertension…
Renal Denervation Reduces Recurrent Atrial Fibrillation 1.2 Freedom from recurrent > 30 seconds atrial fibrillation, off drug therapy 1 0.8 p = 0.033 Renal 0.6 denervation 0.4 No denervation 0.2 0 Baseline 6 months 12 months 27 patients with symptomatic AF and refractory hypertension after pulmonary vein isolation and ablation, with or without renal denervation Pokushalov E. J Am Coll Cardiol 2012; 60:1163-70
Renal Denervation and Diabetes Small trials have shown: Reduction in fasting insulin Reduction in C-peptide Reduction in fasting glucose
Renal Denervation: Change in Glucose, Insulin, C-peptide, and Insulin resistance Fasting insulin Fasting glucose C-peptide HOMA insulin resistance Mahfoud F et al. Circulation 2011;123:1940-1946
Glucose Tolerance After Renal Denervation Mahfoud F et al. Circulation 2011;123:1940-1946
Renal Nerves Interact With Immune Cells macrophage macrophage Afferent nerves in green Efferent nerves in red 50 microns macrophage Macrophages in blue macrophage Veelken R et al. JASN 2008;19:1371-1378
Limitations of Completed Renal Denervation Trials Number of patients too small.
Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short.
Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias).
Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized.
Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized. Efficacy based on office blood pressures… Much poorer response by 24 hour ambulatory BP monitoring...
Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized. Efficacy based on office blood pressures… Much poorer response by 24 hour ambulatory BP monitoring... No morbidity benefit seen.
Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized. Efficacy based on office blood pressures… Much poorer response by 24 hour ambulatory BP monitoring... No morbidity benefit seen. Med changes not allowed during the trials.
Effects of Renal Denervation on Plasma Vasopressin After 20% Hemorrhage Control sheep Renal denervated sheep Smith F G , Abu-Amarah I Am J Physiol Heart Circ Physiol 1998;275:H285-H291
Effects of Renal Denervation of Response to Hemorrhage in Sheep 0% hemorrhage 10% hemorrhage 20% hemorrhage Smith F G , Abu-Amarah I Am J Physiol Heart Circ Physiol 1998;275:H285-H291
Renal Denervation: The Future Larger hypertension trials underway: Other devices: ultrasound, cryoablation, drug injection Longer follow-up being obtained With 24 hour ambulatory BP endpoint “Hard” outcomes Other diseases being studied: heart failure arrhythmia: atrial fibrillation, ventricular tachycardia diabetes, hyperglycemia, and “pre-diabetes” nephroprotection sleep apnea polycystic ovary syndrome ? Inappropriate ADH ? Glomerulonephritis

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Dr.Wright_RenewalofanOldConceptInHypertension_SJMCCardiovascularSymposium

  • 1.
    Renewal of AnOld Concept in Hypertension: The Kidney-Brain Connection Richard F. Wright, MD, FACC Pacific Heart Institute Santa Monica, California
  • 2.
    Richard F. Wright,M.D. Disclosures Speaking Consulting Research Stock Expert Witness Novartis x x St. Jude Medical x x Boston Scientific x Boeringer-Ingelheim x Glaxo Smith Kline x x Takeda x LipoScience x x Medicare/Palmetto x American College of Cardiology x Leading Cardiologists of America x
  • 3.
    What Medical DiagnosisDid These Leaders Share?
  • 4.
  • 5.
  • 6.
    Severe Hypertension… 160/90 190/95 160/110 All three died of stroke…
  • 7.
    A Patient WithResistant Hypertension: Franklin Delano Roosevelt
  • 8.
    Resistant Hypertension: Franklin Delano Roosevelt Last blood pressure the day he died in 1945: 300/190
  • 9.
    Evolution of Antihypertensive Therapy 1940s 1950 1957-1959 1960s 1970s 1980s 1990s 2000’s Direct ACE ARBs Direct renin vasodilators inhibitor inhibitors Thiazide-type Endothelin Peripheral α-blockers blockers* sympatholytics diuretics Ganglion blockers VPIs* Spironolactone Dihydropyridine Veratrum Devices* alkaloids Central α2 CCB’s Sedatives agonists Renal denervation* General anesthesia Calcium channel blockers β-blockers *Not currently approved for clinical use.
  • 10.
    Mortality Benefit ofLowering Blood Pressure CV mortality risk (odds ratio) 1.50 MIDAS/NICS/VHAS Actively controlled trials (ratio experimental/control) UKPDS C vs A Odds ratios >1 Placebo-controlled studies indicate higher or trials with an untreated 1.25 INSIGHT relative risk on control group NORDIL CV Mortality Risk HOT L vs H experimental STOP2/ACEIs treatment HOT M vs H 1.00 MRC2 STOP2/CCBs MRC1 SHEP HEP 0.75 STONE RCT70–80 HOPE Syst-Eur CAPPP UKPDS L vs H Syst-China EWPHE 0.50 PART2/SCAT STOP1 ATMH Negative BP 0.25 values indicate tighter BP regulation on control treatment 0 –5 0 5 10 15 20 25 Difference in office Systolic BP (mmHg) (CONTROL treatment BP minus EXPERIMENTAL treatment BP) 10 Adapted from Staessen JA et al. Hypertens Res. 2005;28:385–407.
  • 11.
    BP Control UsuallyRequires Combination Therapy
  • 12.
    Resistant Hypertension Diagnostic and Treatment Algorithm Confirm treatment resistance Improve lifestyle BP >140/90 Weight loss; Exercise and Ultra-low sodium diet On 3 meds at good doses, including thiazide-type diuretic; Eliminate BP raising substances: or on 4 or more meds NSAIDS, sympathomimetics (eg. Exclude “pseudoresistance” decongestants), contraceptives, Licorice, Ephedra, Cocaine Taking medications? Check 24 hour ambulatory BP BP=Blood pressure Adapted from: Calhoun DA et al. Circulation 2008;117(25):e516
  • 13.
    Resistant Hypertension, continued Diagnostic and Treatment Algorithm Look for Direct Cause of Hypertension Adjust Pharmacologic Treatment Mineralocorticoid blocker Hyperaldosteronism (eg. spironolactone) Sleep apnea Maximize or change diuretic Renal artery stenosis Use even more agents Pheochromocytoma Try “unusual” BP lowering drugs Cushing’s syndrome Aortic coarctation Refer to hypertension specialist Emerging therapies: ? Renal denervation ? Baroreceptor stimulation Adapted from: Calhoun DA et al. Circulation 2008;117(25):e516
  • 14.
    Resistant Hypertension, continued Diagnostic and Treatment Algorithm Look for Direct Cause of Hypertension Adjust Pharmacologic Treatment Mineralocorticoid blocker Hyperaldosteronism (eg. spironolactone) Sleep apnea Maximize or change diuretic Renal artery stenosis Use even more agents Pheochromocytoma Try “unusual” BP lowering drugs Cushing’s syndrome Aortic coarctation Refer to hypertension specialist Emerging therapies: ? Renal denervation ? Baroreceptor stimulation Adapted from: Calhoun DA et al. Circulation 2008;117(25):e516
  • 15.
    Renal Sympathetic EfferentActivity: Brain-to-Kidney Adregergic receptors
  • 16.
    Renal Sympathetic AfferentActivity: Kidney-to-Brain
  • 17.
  • 18.
    Renal Denervation: AnOld Idea Smithwick subsequently utilized bilateral lumbodorsal sympathectomy and splanchnicectomy for reduction of blood pressure…
  • 19.
    Renal Denervation: AnOld Idea Smithwick RH. Am J Med. 1948;4:744-759
  • 20.
  • 21.
    Renal Denervation: AnOld Idea 70-90% death rate at 5 years on “medical therapy”
  • 22.
    Renal Denervation: AnOld Idea 20% death rate at 5 years with surgical denervation 70% death rate on medical therapy
  • 23.
    Surgical Renal Denervation Veryeffective in lowering blood pressure…
  • 24.
    Surgical Renal Denervation Veryeffective in lowering blood pressure… but – High morbidity and mortality after surgery – Long-term damage: severe hypotension, syncope, ileus, incontinence, erectile dysfunction
  • 25.
    Surgical Renal Denervation Veryeffective in lowering blood pressure… but – High morbidity and mortality after surgery – Long-term damage: severe hypotension, syncope, ileus, incontinence, erectile dysfunction Therefore, abandoned upon the development of tolerable and effective medical therapies after 1957…
  • 26.
    Renal Inervation Renal nerves: •Arise from T10 - L1 • Course along the renal pedicle • Follow the renal artery to the kidney • Lie within the artery adventitia
  • 27.
    Renal Inervation Renal nerves: •Arise from T10 - L1 • Course along the renal pedicle • Follow the renal artery to the kidney • Lie within the artery adventitia
  • 28.
    Renal Nerves AreIn The Adventitia
  • 29.
    Effect of RenalNerve Stimulation Efferent stimulation: Sodium and water retention Increased renin release Afferent stimulation: Increases central sympathetic output
  • 30.
    Renal Innervation: Effect of Surgical Denervation Efferent nerves (in red) Afferent nerves (in green) Renal parenchyma Renal artery adventitia 2 days after unilateral denervation Non-denervated side Veelken R et al. JASN 2008;19:1371-1378
  • 31.
    Afferent Renal Nerves Nervecell bodies in the dorsal ganglia Fiber endpoints throughout the kidney: Highest density in the renal pelvis – Mechano-receptors: renal pelvis renal arteries renal veins – Chemo-sensors: interstitial oxygen blood flow pH and local chemistry
  • 32.
    Renal Artery SympatheticDenervation Animal Models: • Spontaneously hypertensive (SHR) rat • Stroke Prone SHR (rat) • New Zealand SHR (rat) • Goldblatt 1Kidney, 1C (rat) • Goldblatt 2Kidney, 2C (rat) • Aortic coarctation (dog) • Aortic nerve transection (rat) • DOCA-NaCl (rat, pig) • Angiotensin II infusion (rat, rabbit) • Fat feeding - Obesity (dog) • Renal wrap (rat) DiBona et al. Physiol Rev. 1997;77:175-197
  • 33.
    Renal Artery SympatheticDenervation Animal Models: • Spontaneously hypertensive (SHR) rat • Stroke Prone SHR (rat) • New Zealand SHR (rat) • Goldblatt 1Kidney, 1C (rat) In every model, • Goldblatt 2Kidney, 2C (rat) renal denervation • Aortic coarctation (dog) lowers blood • Aortic nerve transection (rat) pressure • DOCA-NaCl (rat, pig) • Angiotensin II infusion (rat, rabbit) • Fat feeding - Obesity (dog) • Renal wrap (rat) DiBona et al. Physiol Rev. 1997;77:175-197
  • 34.
    Renal Artery SympatheticEffects, Other Animal Observations: Stimulation of renal afferent nerve raises blood pressure in dogs
  • 35.
    Renal Sympathetic Denervation Human Observations: • Nephrectomy lowers blood pressure • Renal transplant patients remain hypertensive if failed kidneys are left in place • Reimplantaion of own kidney lowers blood pressure
  • 36.
    Renal Artery ElectricalStimulation Increases Blood Pressure in Humans 35 mm Hg high frequency renal artery stimulation pressure, mmHg, after 10 seconds of Change in central systolic arterial 30 p < 0.001 25 Before renal 20 denervation 15 10 After denervation 5 0 1 2 3 4 5 minutes 27 patients with symptomatic AF and refractory hypertension Pokushalov E. J Am Coll Cardiol 2012; 60:1163-70
  • 37.
    Renal Nerve AfferentSympathetic Traffic • None in normal people • High in: – Renal artery stenosis – Heart failure – Metabolic syndrome – Obese – Insulin resistance and diabetics – Hypertension
  • 38.
  • 39.
  • 40.
    Catheter-based Renal Denervation Kidney 4 to 6 lesions per renal artery depending on length of artery; usually, bilateral procedure Aorta
  • 41.
  • 42.
  • 43.
    Renal Artery Histology6 Months After Ablation Movat’s pentachrome stain , pigs cutting artifact Zone of energy delivery 20X magnification 100X magnification Minimal intimal thickening and minimal IEL injury overlying areas of mild full thickness medial fibrosis (yellow with green [proteoglycan deposition]), and adventitial fibrosis (yellow). No significant inflammatory cells present.
  • 44.
    Renal Denervation: Effecton Sympathetic Tone Schlaich M. N Engl J Med. 2009
  • 45.
    (Symplicity HTN-1) • First-in-man 12-month evaluation of percutaneous renal sympathetic denervation in patients with “refractory hypertension.“ • No control group. • Inclusion Criteria: – Office systolic BP ≥160 mmHg despite 3+ anti-hypertensive meds (including a diuretic), or confirmed intolerance to medications – FR (MDRD formula) of ≥ 45 mL/min/1.73m2 • Exclusion Criteria: – Secondary cause of hypertension, or Type I diabetes – Current administration of clonidine, moxonidine, or rilmenidine – Renal artery stenosis, stenting or angioplasty; dual renal arteries Lancet 2009 Apr 11;373(9671):1275-81
  • 46.
    Patients Undergoing Procedure:n=45 Anatomically Ineligible: n=5 Age (years) 58 ± 9 51 ± 8 Gender (% female) 44 20 Race (%non-Caucasian) 4 0 Diabetes Mellitus(%) 31 40 CAD (%) 22 20 Heart Rate (bpm) 72 ± 11 79 ± 9 eGFR (mL/min/1.73m2) 81 ± 23 95 ± 15 Office BP (mmHg) 177/101 ± 20/15 173/98 ± 8/9 Number of BP meds (mean) 4.7 ± 1.5 4.6 ± 0.5 ACE/ARB (%) 96 80 Beta-blocker (%) 76 100 Calcium channel blocker (%) 69 100 Vasodilator (%) 18 0 Diuretic (%) 96 60
  • 47.
    • No evidentcomplication in 43 of 45 patients: – 1 renal artery dissection during renal catheterization (before RF energy) – 1 femoral artery pseudoaneurysm • No long-term vascular complications observed: – 18 patients with follow-up angiograms (14-30 days post-procedure) – 31 with MRA or CTA at 6-months post-procedure • 4.7 ± 1.5 anti-hypertensive drugs at baseline; unchanged at follow-up • 3 patients required reduction of medications after normalization of BP • 9 patients had their medications increased: – 5 were BP responders: >10mmHg BP reduction prior to med increase – 4 were BP non responders Lancet 2009 Apr 11;373(9671):1275-81
  • 48.
    Symplicity HTN-1: BP Reductions Through 3 years 0 -5 -10 -9 BP change -10 -10 (mmHg) -12 -15 -13 -14 -15 -20 -19 -19 -21 -22 -25 Systolic BP -26 -26 Diastolic BP -30 -35 -33 -33 -33 P<0.01 for ∆ from BL for all time points 1M 3M 6M 12 M 18 M 24 M 30 M 36 M (n=143) (n=148) (n=144) (n=130) (n=107) (n=59) (n=24) (n=24) *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)
  • 49.
    The Symplicity HTN-2Trial Randomized trial of catheter-based renal denervation • 106 pts randomized 1:1 to renal denervation vs. control • 24 centers in Europe, Australia, & New Zealand (67% were hypertension centers of excellence). • PRIMARY ENDPOINT: Office systolic BP change, 6 months • SECONDARY ENDPOINTS: Safety and procedural issues 6-month: Renovascular & kidney function Composite CV endpoint BP reduction, 24 hour Ambulatory BP monitoring LV function and mass by cardiac MRI Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
  • 50.
    The Symplicity HTN-2Trial • Inclusion Criteria: – Office SBP 160 mmHg ( 150 mmHg if type II diabetic) Actual randomized baseline BP: 178/97 – > 3 anti-hypertensive meds, on stable medical regimen Actual mean number of meds: 5.2 (2/3 on 5 or more) – Age 18-85 years and estimated GFR > 45 mL/min/1.73m2 • Exclusion Criteria: – No significant renal artery abnormalities or prior intervention – Type I diabetes – Contraindication to MRI – MI, unstable angina, or CVA in the prior 6 months – Pregnancy Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
  • 51.
    Centers: Symplicity HTN-2 Europe & Australia/NZ Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
  • 52.
    The Symplicity HTN-2Trial: 6-Month Office Blood Pressure Results RDN (n=49) Control (n=51) 10 ∆ from 1 Baseline 0 0 to 6 Months Diastolic Systolic Diastolic -10 (mmHg) -12 -20 -30 Systolic -32 -40 p<0.0001 vs. control -50 • 84% of RDN patients had ≥ 10 mmHg reduction in SBP • 10% of RDN patients had no reduction in SBP Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
  • 53.
    The Symplicity HTN-2Trial: Results Esler M, Lancet, 2011;376:1074-1075
  • 54.
    Symplicity HTN-2: Renal Function Results Treated at Randomization Randomized Baseline 6 month 12 months N=47 eGFR (ml/min/1.73m2) 76.9 ±19.3 (n= 49) 77.1±18.8 (n=49) 78.2±17.4 (n=45) Cystatin C (mg/L) 0.91±0.25 (n=38) 0.98±0.36 (n=40) 0.98±0.30 (n=38) Treated after 6-mo follow-up Crossover Baseline 6 month 12 months N=35 eGFR (ml/min/1.73m2) 88.8 ± 20.7 (n = 35) 89.3±19.5 (n = 35) 85.2±18.3 (n = 35) Cystatin C (mg/L) 0.78 ± 0.17 (n=27) 0.82±0.16 (n=26) 0.89±0.20 (n=26)
  • 55.
    The Symplicity HTN-2Trial: Results Mean change in office BP at 6 months: Denervation patients: 32/12 mmHg Control patients: -1/0 mmHg p=0.001 Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
  • 56.
    The Symplicity HTN-2Trial: Results Mean change in office BP at 6 months: Denervation patients: -32/12 mmHg Control patients: -1/0 mmHg p=0.001 24-hour ambulatory BP results: • Renal denervation: -11/-7 mmHg p=0.006 systolic • Control: -3/ -1 mmHg p=0.51 for systolic No change in estimated GFR, serum creatinine, or cystatin C at 6 months Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
  • 57.
    The Symplicity HTN-2Trial: Safety Device or procedure related adverse events (total n=52): 2 minor adverse events: • 1 femoral artery pseudoaneurysm • 1 reduction in BP requiring reduction in BP medication 6-month renal imaging (n=43, 37 Duplex echo, 5 MRI, 5 CT): • No new renal vascular abnormality • Progression of a pre-existing renal artery stenosis in 1 patient (thought unrelated to ablation ) Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
  • 58.
    Renal Denervation ReducesLeft Ventricular Hypertrophy 16 14 p = 0.007 Baseline 12 1 month 10 6 months 8 Septal thickness, Septal thickness, Septal thickness, mm mm mm 46 patients after renal denervation: BP reduced 27/8.8 mmHg at 6 months Brandt MD. J Am Coll Cardiol 2012; 59:901-909
  • 59.
    Renal Denervation ReducesLeft Ventricular Hypertrophy 60 55 50 p < 0.0001 Baseline 45 1 month 40 35 6 months 30 LV mass index, LV mass index, LV mass index, g/m2 g/m2 g/m2 46 patients after renal denervation: BP reduced 27/8.8 mmHg at 6 months Brandt MD. J Am Coll Cardiol 2012; 59:901-909
  • 60.
    Eligibility for RenalDenervation in Resistant Hypertension: Enthusiasm Meets Reality Diagram showing patient screening for renal denervation in accordance with a European Society of Hypertension position paper. BP = blood pressure; eGFR = estimated glomerular filtration rate; HTN = hypertension. S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
  • 61.
    Eligibility for RenalDenervation in Resistant Hypertension: Enthusiasm Meets Reality S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
  • 62.
    Eligibility for RenalDenervation in Resistant Hypertension: Enthusiasm Meets Reality S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
  • 63.
    Eligibility for RenalDenervation in Resistant Hypertension: Enthusiasm Meets Reality 1,209 potential patients became 15 “eligible” patients… S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
  • 64.
    Renal Artery StenosisAfter Ablation B. Kaltenbach, J Am Coll Cardiol. 2012;60(25):2694-2695
  • 65.
    Renal Denervation: Utility inDisease States Other Than Hypertension…
  • 66.
    Renal Denervation Reduces Recurrent Atrial Fibrillation 1.2 Freedom from recurrent > 30 seconds atrial fibrillation, off drug therapy 1 0.8 p = 0.033 Renal 0.6 denervation 0.4 No denervation 0.2 0 Baseline 6 months 12 months 27 patients with symptomatic AF and refractory hypertension after pulmonary vein isolation and ablation, with or without renal denervation Pokushalov E. J Am Coll Cardiol 2012; 60:1163-70
  • 67.
    Renal Denervation andDiabetes Small trials have shown: Reduction in fasting insulin Reduction in C-peptide Reduction in fasting glucose
  • 68.
    Renal Denervation: Changein Glucose, Insulin, C-peptide, and Insulin resistance Fasting insulin Fasting glucose C-peptide HOMA insulin resistance Mahfoud F et al. Circulation 2011;123:1940-1946
  • 69.
    Glucose Tolerance AfterRenal Denervation Mahfoud F et al. Circulation 2011;123:1940-1946
  • 70.
    Renal Nerves InteractWith Immune Cells macrophage macrophage Afferent nerves in green Efferent nerves in red 50 microns macrophage Macrophages in blue macrophage Veelken R et al. JASN 2008;19:1371-1378
  • 71.
    Limitations of Completed Renal Denervation Trials Number of patients too small.
  • 72.
    Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short.
  • 73.
    Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias).
  • 74.
    Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized.
  • 75.
    Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized. Efficacy based on office blood pressures… Much poorer response by 24 hour ambulatory BP monitoring...
  • 76.
    Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized. Efficacy based on office blood pressures… Much poorer response by 24 hour ambulatory BP monitoring... No morbidity benefit seen.
  • 77.
    Limitations of Completed Renal Denervation Trials Number of patients too small. Follow-up too short. Open studies (potential bias). Treatment not standardized. Efficacy based on office blood pressures… Much poorer response by 24 hour ambulatory BP monitoring... No morbidity benefit seen. Med changes not allowed during the trials.
  • 78.
    Effects of RenalDenervation on Plasma Vasopressin After 20% Hemorrhage Control sheep Renal denervated sheep Smith F G , Abu-Amarah I Am J Physiol Heart Circ Physiol 1998;275:H285-H291
  • 79.
    Effects of RenalDenervation of Response to Hemorrhage in Sheep 0% hemorrhage 10% hemorrhage 20% hemorrhage Smith F G , Abu-Amarah I Am J Physiol Heart Circ Physiol 1998;275:H285-H291
  • 80.
    Renal Denervation: TheFuture Larger hypertension trials underway: Other devices: ultrasound, cryoablation, drug injection Longer follow-up being obtained With 24 hour ambulatory BP endpoint “Hard” outcomes Other diseases being studied: heart failure arrhythmia: atrial fibrillation, ventricular tachycardia diabetes, hyperglycemia, and “pre-diabetes” nephroprotection sleep apnea polycystic ovary syndrome ? Inappropriate ADH ? Glomerulonephritis