postural tachycardia syndrome (pots) – what? why? how?case presentation – ap (2) position hr...
TRANSCRIPT
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Postural Tachycardia Syndrome (POTS) – What? Why? How?
Satish R Raj MD MSCI FACC FHRS FRCPC Associate Professor of Cardiac Sciences University of Calgary Adjunct Associate Professor of Medicine Autonomic Dysfunction Center Vanderbilt University School of Medicine October 2014
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Case Presentation - AP n ONSET
q Age 26 years; SWF; works in music industry q Dx “Pneumonia” -> inhalers q Developed “spells of tachycardia” q Cardiologist #1 proposed EP Study/Ablation q Cardiologist #2 -> Tilt Test q Associated Symptoms
n Lightheaded/presyncope (standing) n Intermittent stabbing chest pains (standing) n Mental clouding (“brain fog”) n Severe fatigue
SR Raj, Circulation 2013
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Case Presentation – AP (2)
Position HR (bpm) BP (mmHg) Supine – 15 min 73 103/72 Upright – 1 min 106 109/80 Upright – 3 min 105 106/83 Upright – 5 min 122 118/75
Upright – 10 min 121 118/78
Orthostatic Challenge
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WHAT is POTS?
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Postural Tachycardia Syndrome - Common Criteria
n Orthostatic tachycardia > 30 bpm q >40 bpm required if <18 years
n No consistent orthostatic hypotension q ΔBP > 20/10 mmHg
n Symptoms of sympathetic activation q Worse upright; better recumbent
n Chronic symptoms > 6 months
Phillip Low MD Mayo Clinic
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POTS - Mimics & Associations n Mimics
q Acute infections q Multiple sclerosis q Sjogren’s syndrome
n Associations q Joint Hypermobility Syndrome
n Ehlers Danlos Syndrome – Hypermobility q Fibromyalgia q Chronic Fatigue Syndrome
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POTS - Common Symptoms
n Rapid Heartbeat n Chest Discomfort n Short of Breath n Lightheaded
n Exercise Intolerance
n Mental Clouding n Headache n Nausea n Tremulousness
n Fatigue n Sleep Complaints
Cardiac Non-Cardiac
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POTS Control Heart Rate (bpm)
Blood Pressure (mmHg)
Tilt Angle (deg)
200
200 0
50
60
0
Tilt Testing
SR Raj, Indian Pacing Electrophysiol J. 2006;6:84-99
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POTS: Feel awful when upright
0 10 20 30
05
101520253035
POTSControl
Tilt (60°) Time
Sym
ptom
s S
core
(au
)
SR Raj & RS Sheldon, Tilt Table Testing in S Saksena & AJ Camm Electrophysiological Disorders of the Heart 2nd Ed. (2011)
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POTS – Who is affected?
n Prevalence ½ million in USA n Female (~80-85%) n Typically aged 13-50 years
n Significant functional disability
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Quality of Life in POTS
Kanika Bagai
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Health Related Quality of Life (SF-36) – Chronic Illnesses
Physical Mental0
25
50
75
100 Back PainESRD
SF36 Sub-Scores
Scor
eDialysis
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Health Related Quality of Life (SF-36) – Chronic Illnesses
Physical Mental0
25
50
75
100
POTSBack PainESRD
SF36 Sub-Scores
Scor
e
Modified from K Bagai et al., J Clin Sleep Med 2011
Dialysis
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Sleep Problems Correlate with Poor HRQL
HealthyPOTS
0 25 50 75 100MOS Sleep Problems Index
10
20
30
40
50
60
70
SF36
Phy
sica
l
R-Square = 0.62
HealthyPOTS
0 25 50 75 100MOS Sleep Problems Index
10
20
30
40
50
60
SF36
Men
tal
R-Square = 0.60
Physical Mental
R2=0.62 R2=0.60
Modified from K Bagai et al., J Clin Sleep Med 2011
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WHY do they have POTS?
… ‘final common pathway’ of hundreds of genetic and acquired autonomic and cardiovascular entities
- David Robertson
David Robertson
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Pathophysiology of POTS – The Challenge
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Blind men and the Elephant n It was six men of Hindustan
To learning much inclined, Who went to see the Elephant (Though all of them were blind), That each by observation Might satisfy his mind
n They conclude that the elephant is like a wall, snake, spear, tree, fan or rope, depending upon where they touch.
Ancient Hindu Parable retold by John Godfrey Saxe (1816–1887)
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Pathophysiology of POTS
Satish
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POTS - Pathophysiologies
n Mast Cell Activation n Partial Autonomic Neuropathy n Leg Blood Flow Abnormalities n Hypovolemia n Hyperadrenergic
q Increased Release q Decreased Clearance
n Antibodies are Evil…
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POTS and Mast Cells
n Spot (4 hour) urine collection n If syncopal/flushing attack, 1-2 hour urine
collection n Mast cell activation disorder n Often aspirin sensitivity n Therapy:
q H1 + H2 blockade q ASA q Alpha-methyldopa Italo Biaggioni
C Shibao et al., Hypertension 2005
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Neuropathic POTS
Normal nPOTS Giris Jacob
§ Reduced NE Spillover in legs
§ Abnormal sweat test (QSART) in legs
G Jacob et al., N Engl J Med. 2000;343:1008-14
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Leg Blood Flow May Identify Different Subpopulations of POTS
Julian Stewart
Stewart J M et al. AJP Heart Circ Physiol 2003;285:H2749-H2756
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Blood Volume & Renin-Angiotensin-Aldosterone System in POTS
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Plasma Volume is Low in POTS
Adapted from SR Raj et al., Circulation 2005;111:1574-1582
Control POTS
-25-20-15-10-505
1015
P<0.001
PV D
evia
tion
(%)
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Plasma Renin Activity & Aldosterone are inappropriately low in POTS…when one would expect them elevated
Supine Standing0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5 P=0.941P=0.996POTS Control
Ren
in ((
ng/m
l)/hr
)
Supine Standing0
250
500
750
1000POTS Control
Ald
oste
rone
(pM
)
P=0.019P=0.017
Adapted from SR Raj et al., Circulation 2005;111:1574-1582
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RAAS Schema in POTS
AGT ANG I ANG II Aldo
Blood Volume
PRA ACE
ANG (1-7) ACE2
Adapted from HI Mustafa et al., Heart Rhythm. 2011;8:422-8.
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Conclusions – RAAS in POTS n Things are screwy n Unusual RAAS profile in POTS
q Low blood volume q Low plasma renin activity q Low aldosterone
n More work is needed to understand physiology q Decreased ACE2 activity? q Elevated ANG II due to less degradation? q Why are aldosterone levels low?
n Can the kidney not hold onto sodium in POTS? q May explain the need for high sodium diets and low
blood volume in POTS.
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Hyperadrenergic POTS – Increased SNS Nerve Firing
Normal hPOTS
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Hyperadrenergic POTS – Decreased NE Clearance
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A Norepinephrine Synapse
NET
Slide courtesy of Alex Nackenoff
(Vanderbilt)
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A Norepinephrine Synapse
NET
Slide courtesy of Alex Nackenoff
(Vanderbilt)
SNS Tone
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Shannon JR, NEJM 2000; 342:541-9.
.
P
P P P
P
S-S
P
V69I
T99I
V245IV449I
G478SA457PN292T
V356L
A369P N375S
K463R
F528C
Y548H
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Reaction at Vanderbilt
n Excitement
n The cause of POTS has been found!!!
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POTS Patients with NET mutations: 2000-2010
n n n n
No other patients had this mutation. We had just about given up hope in NET defects as a cause of POTS…
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Variable Expression of NET Protein in POTS
Courtesy of Murray Esler, Baker IDI (Melbourne, Australia)
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Lambert E et al. Circ Arrhythm Electrophysiol 2008;1:103-109
Decreased NET Protein Expression in some POTS Patients
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Role of Antibodies in POTS
1. AChR Antibody 2. Adrenergic Antibodies
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Ganglionic Acetylcholine Receptor Ab n Discovered at Mayo Clinic
q Steve Vernino & Vanda Lennon
n Loss of function Ab at Autonomic Ganglia
n Prevalence in POTS q Mayo: ~7-14% of POTS patients
n Now reportedly lower per Dr. P Low (Mayo)
q Vanderbilt: 0% of POTS patients
n Presentation is usually Autonomic Failure q Orthostatic hypotension q Constipation, pupil findings
Schroeder C et al. NEJM 2005;353:1585-1590
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POTS Patient serum stimulates adrenergic receptors
H Li et al., JAHA 2014; 3(1):e000755.
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Beta-receptor activation from POTS sera β2
-AR
med
iate
d
cAM
P re
leas
e β1
-AR
med
iate
d
cAM
P re
leas
e
H Li et al., JAHA 2014; 3(1):e000755.
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The Model
How could the Ab contribute to the POTS phenotype?
H Li et al., JAHA 2014; 3(1):e000755.
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POTS – HOW to Manage?
Investigation & Treatment
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POTS: Investigations
n History & Physical Examination n Orthostatic Vital Signs n CBC, BMP n Autonomic Reflex Testing n Echocardiogram n Blood Volume Assessment n Exercise Capacity Assessment
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POTS: Treatment Approaches n Exercise n Increase Blood Volume
q Oral Water q Increase Salt (diet vs. tablets) q Fludrocortisone q Octreotide q IV Saline q Acute DDAVP-H2O
n Hemodynamic Agents q Midodrine q Propranolol q Pyridostigmine q Ivabradine (emerging)
n Behavioral Therapies
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Exercise in POTS
n Historically q “good thing to do” q Many patients could not/would not
n excessive fatigue (~days) and intolerance q Anecdotally, those patients that did exercise
did better over time n Cause/effect vs. selection bias
n Now q Recent data on effects of exercise training in
POTS from Dallas, Vienna, & Mayo…
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Exercise Study in POTS - Design
Screening
Blood Volume Measurement
Maximal Exercise Test
45-min 60° Upright Tilt
Cardiac MRI
Maximal Exercise Test
45-min 60° Upright Tilt
Blood Volume Measurement
Cardiac MRI
3 months of exercise training
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Exercise in POTS - Benefits
n Short-term exercise training in POTS q Increases fitness levels q Increases blood volume q Cardiac Remodeling q Normalizes Sympathetic Activity q Decreases Orthostatic Tachycardia
Qi Fu et al., JACC 2010;55:2858-68
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Exercise in POTS – How To? n Focus on Aerobic Activity
q Some resistance training focused on thighs n Must be Regular
q Every other day (4/week) n 30min/session -> 45-60min/session n NO UPRIGHT EXERCISES
q Rowing machines q Recumbent Cycles q Swimming
n Takes 4-5 weeks to start seeing benefits Qi Fu et al., JACC 2010;55:2858-68
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POTS: Treatment Approaches n Exercise n Increase Blood Volume
q Oral Water q Increase Salt (diet vs. tablets) q Fludrocortisone q Octreotide q IV Saline q Acute DDAVP-H2O
n Hemodynamic Agents q Midodrine q Propranolol q Pyridostigmine q Ivabradine (emerging)
n Behavioral Therapies
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G Jacob et al. Circulation 1997;96:575-580
IV Saline (1L) Acutely Decreases Orthostatic Tachycardia…a LOT!!
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DDAVP+H2O reduces standing HR
Pre 1H 2H 3H 4H859095
100105110115120125 DDAVP+H2O Placebo
PTime=0.001
PDrug=0.001
PINT =0.001
Time Post Dose
Hea
rt R
ate
(bpm
)
ST Coffin et al., Heart Rhythm. 2012;9:1484-90
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POTS: Treatment Approaches n Exercise n Increase Blood Volume
q Oral Water q Increase Salt (diet vs. tablets) q Fludrocortisone q Octreotide q IV Saline q Acute DDAVP-H2O
n Hemodynamic Agents q Midodrine q Propranolol q Pyridostigmine q Ivabradine (emerging)
n Behavioral Therapies
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Jacob, G. et al. Circulation 1997;96:575-580
Midodrine Decreases Orthostatic Tachycardia…a little bit.
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Beta-Blockers in POTS
n PRO q Intuitively appealing
n High HR -> Lower it
n CON q Stewart et al. studied IV esmolol and found
that it DID NOT improve orthostatic tolerance q Many patients report “intolerance to beta-
blockers”
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Pre 1H 2H 3H 4H70
80
90
100
110
120
130 Propranolol Placebo
PDrug <0.001PInt <0.001
Time Post Dose
Hea
rt R
ate
(bpm
)Propranolol 20mg lowers Orthostatic Tachycardia
Pre 1H 2H 3H 4H0
10
20
30
40 Propranolol Placebo
PDrug <0.001
Time Post Dose
Cha
nge
in H
eart
Rat
e (b
pm)
Standing HR Orthostatic Increase in HR
SR Raj et al. Circulation 2009;120:725-734
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Symptoms
Pre 2H 4H12
14
16
18
20
22
24
26 Propranolol Placebo
PInt =0.04
Time Post Dose
Sym
ptom
s (a
.u.)
Propranolol Improves Symptoms…
SR Raj et al. Circulation 2009;120:725-734
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Propranolol 20mg Propranolol 80mg
-15
-10
-5
0
P =0.041Wilcoxon
Δ S
ympt
oms
Scor
e (a
.u.)
…but Less is More
SR Raj et al. Circulation 2009;120:725-734
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Acetylcholinesterase Inhibition
n Pyridostigmine q Peripheral AChEI q Increases availability of synaptic ACh q Ganglionic Nicotinic Receptor
n ↑ SNS & ↑ PNS q Postganglionic Muscarinic Receptor
n ↑ PNS
n Might decrease tachycardia in POTS
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Pre 2H 4H9095
100105110115120125130135 Pyridostigmine Placebo
P=0.001 P=0.160
P<0.001
P<0.001
Time Post Dose
Hea
rt R
ate
(bpm
)Acetylcholinesterase Inhibition
Standing Heart Rate Symptoms
SR Raj et al., Circulation 2005;111:2734-2740
Pyridostigmine Placebo
-15
-10
-5
0
5
P=0.025
Cha
nge
in S
ympt
om S
core
(au)
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Norepinephrine Transporter Inhibition
Standing
Pre 1H 2H 3H 4H90
100
110
120
130 Atomoxetine Placebo
PInt <0.001
A
Time Post Dose
Hea
rt R
ate
(bpm
)
EA Green et al., JAHA 2013;2:e000395
Seated
Pre 1H 2H 3H 4H70
75
80
85
90
95
100
PInt =0.029
B
PlaceboAtomoxetine
Time Post Dose
Hea
rt R
ate
(bpm
)
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Norepinephrine Transporter Inhibition
Orthostatic Change
Pre 1H 2H 3H 4H15
20
25
30
35
40 Atomoxetine Placebo
PInt =0.001
C
Time Post Dose
Δ H
eart
Rat
e (b
pm)
Symptoms: 0 to 2h
Atomoxetine Placebo
-8
-6
-4
-2
0
2
4
6
P =0.028Δ
Sym
ptom
s Sc
ore
(a.u
.)
EA Green et al., JAHA 2013;2:e000395
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POTS: Treatment Approaches n Exercise n Increase Blood Volume
q Oral Water q Increase Salt (diet vs. tablets) q Fludrocortisone q Octreotide q IV Saline q Acute DDAVP-H2O
n Hemodynamic Agents q Midodrine q Propranolol q Pyridostigmine q Ivabradine (emerging)
n Behavioral Therapies
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What Type of POTS Do I Have?
Challenges: 1. Overlapping Subsets 2. Lost in Translation
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Hyperadrenergic POTS Neuropathic POTS
Hypovolemic POTS
What Type of POTS Do I Have?
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Hyperadrenergic POTS Neuropathic POTS
Hypovolemic POTS
What Type of POTS Do I Have?
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Lost in Translation
Not my M-I-L
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Prognosis of POTS
“Prediction is very difficult, especially about the future.” Niels Bohr (1885-1962); Nobel Prize (Physics) 1922
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POTS – Take Home Messages n POTS
q chronic disorder associated with significant disability
q Syndrome…not one disease n Multiple pathophysiologies
n Treatment q Exercise q Volume expansion q Heart rate control q Manage the “living with a chronic illness”
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Questions?