1. Renewal of An Old
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
7. A Patient With Resistant 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 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.
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
18. Renal Denervation: An Old Idea
Smithwick subsequently utilized bilateral lumbodorsal
sympathectomy and splanchnicectomy for reduction of
blood pressure…
24. 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
25. 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…
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
29. Effect of Renal Nerve 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
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
34. Renal Artery Sympathetic Effects,
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 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
37. Renal Nerve Afferent Sympathetic Traffic
• None in normal people
• High in:
– Renal artery stenosis
– Heart failure
– Metabolic syndrome
– Obese
– Insulin resistance and diabetics
– Hypertension
43. 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.
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
47. • 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
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-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
50. 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
52. 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
55. 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
56. 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
57. 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
58. 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
59. 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
60. 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
61. Eligibility for Renal Denervation in Resistant
Hypertension: Enthusiasm Meets Reality
S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
62. Eligibility for Renal Denervation in Resistant
Hypertension: Enthusiasm Meets Reality
S. Savard, J Am Coll Cardiol. 2012;60(23):2422-2424
63. 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
64. Renal Artery Stenosis After Ablation
B. Kaltenbach, J Am Coll Cardiol. 2012;60(25):2694-2695
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 and Diabetes
Small trials have shown:
Reduction in fasting insulin
Reduction in C-peptide
Reduction in fasting glucose
68. 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
70. 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
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 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
79. 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
80. 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
