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POSTURAL TACHYCARDIA SYNDROME (POTS)
WHAT? WHY? HOW?Satish R Raj MD MSCI FACC FHRS FRCPCAssociate Professor of Cardiac Sciences, University of CalgaryAdjunct Associate Professor of Medicine, Autonomic Dysfunction Center, Vanderbilt University School of MedicineOctober 2014
WHAT?
Section 1
SR Raj, Circulation 2013
CASE PRESENTATION – APOnset
• Age 26 years; SWF; works in music industry
• Dx “pneumonia” inhalers
• Developed “spells of tachycardia”
• Cardiologist #1 proposed EP study/ablation
• Cardiologist #2 Tilt Test
• Associated symptoms• Lightheaded/presyncope (standing)• Intermittent stabbing chest pains (standing)• Mental clouding (“brain fog”)• Severe fatigue
CASE PRESENTATION – AP (2)
ORTHOSTATIC CHALLENGE
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
What is POTS?
COMMON CRITERIA• Orthostatic tachycardia >30 bpm• >40 bpm required if <18 years
• No consistent orthostatic hypotension• ΔBP >20/10 mmHg
• Symptoms of sympathetic activation• Worse upright; better recumbent
• Chronic symptoms >6 months
Phillip Low MD,Mayo Clinic
MIMICS AND ASSOCIATIONSMimics
• Acute infections
• Multiple Sclerosis
• Sjogren’s Syndrome
Associations
• Joint Hypermobility Syndrome• Ehlers Danlos Syndrome – Hypermobility
• Fibromyalgia
• Chronic Fatigue Syndrome
COMMON SYMPTOMS
CARDIAC
• Rapid heartbeat
• Chest discomfort
• Short of breath
• Lightheaded
• Exercise intolerance
NON-CARDIAC
• Non-cardiac
• Mental clouding
• Headache
• Nausea
• Tremulousness
• Fatigue
• Sleep complaints
Heart Rate (bpm)
Blood Pressure (mmHg)
Tilt Angle (deg)
200
0200
50
60
0
TILT TESTING
POTS CONTROL
SR RAJ, INDIAN PACING ELECTROPHYSIOL J. 2006;6:84-99
FEEL AWFUL WHEN UPRIGHT
SR RAJ & RS SHELDON, S SAKSENA & AJ CAMM TILT TABLE TESTING IN ELECTROPHYSIOLOGICAL DISORDERS OF THE HEART 2ND ED. (2011)
Sym
pto
ms S
core
(au
)
Tilt (60°) Time
0 3010 20
0
5
10
15
20
25
30
35POTS
Control
WHO IS AFFECTED?• Prevalence ½ million in USA
• Female (~80-85%)
• Typically aged 13-50 years
• Significant functional disability
QUALITY OF LIFE IN POTSKanika Bagai
Click icon to add picture
HEALTH RELATED QUALITY OF LIFESF-36 – CHRONIC ILLNESSES
100
Score
SF36 Sub-Scores
75
50
25
0
Physical Mental
Back Pain
Dialysis
Modified from K Bagai et al., J Clin Sleep Med 2011
HEALTH RELATED QUALITY OF LIFESF-36 – CHRONIC ILLNESSES (2)
POTS
100
Score
SF36 Sub-Scores
75
50
25
0
Physical Mental
Back Pain
Dialysis
Modified from K Bagai et al., J Clin Sleep Med 2011
SLEEP PROBLEMS CORRELATE WITH POOR HRQL
PHYSICAL MENTAL
R2=0.62
0 100
10
20
30
40
50
60
70
SF3
6 P
hysic
al
MOS Sleep Problems Index
25 50 75
Healthy
POTS
Healthy
POTS
R2=0.60
SF3
6 M
en
tal
0 100
MOS Sleep Problems Index
25 50 75
10
20
30
40
50
60
WHY?
Section 2
WHY DO THEY HAVE POTS?. . . ‘final common pathway’ of hundreds of genetic and acquired autonomic and cardiovascular entities– David Robertson
PATHOPHYSIOLOGY OF POTS – THE CHALLENGE
Ancient Hindu Parable retold by John Godfrey Saxe (1816–1887)
BLIND MEN AND THE ELEPHANT• 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
• They conclude that the elephant is like a wall, snake, spear, tree, fan
or rope, depending upon where they touch
PATHOPHYSIOLOGY OF POTS
Satish
PATHOPHYSIOLOGIES• Mast Cell Activation
• Partial Autonomic Neuropathy
• Leg blood flow abnormalities
• Hypovolemia
• Hyperadrenergic• Increased release• Decreased clearance
• Antibodies are evil . . .
C Shibao et al., Hypertension 2005
POTS AND MAST CELLS• Spot (4 hour) urine collection
• If syncopal/flushing attack, 1-2 hour urine collection
• Mast Cell Activation Disorder
• Often aspirin sensitivity
• Therapy:• H1 + H2 blockade• ASA• Alpha-methyldopa Italo
Biaggioni
G Jacob et al., N Engl J Med. 2000;343:1008-14
NEUROPATHIC POTS
NORMAL nPOTS
• Reduced NE spillover in legs• Abnormal sweat test (QSART) in legs
Giris JacobGiris Jacob
Stewart J M et al. AJP Heart Circ Physiol 2003;285:H2749-H2756
Julian
StewartJulian
Stewart
LEG BLOOD FLOW MAY IDENTIFY DIFFERENT POTS SUBPOPULATIONS
Control (tau=28s)
Low flow (tau=20s)
High flow (tau=29s)
0 150
Time (sec)
3 100 12525 50 75
Leg
Flo
w (
ml/
10
0m
l/m
in)
10
20
30
0
Blood volume andrenin-angiotensin-aldosterone system in POTS
Adapted from SR Raj et al., Circulation 2005;111:1574-1582
PLASMA VOLUME IS LOW IN POTS
P<0.001
Control POTS
PV
Devia
tion
(%
)
15
10
5
0
-5
-10
-15
-20
-25
Adapted from SR Raj et al., Circulation 2005;111:1574-1582
PLASMA RENIN ACTIVITY AND ALDOSTERONEInappropriately low in POTS, when one would expect them elevated
Supine Standing
0
250
500
750
1,000
Ald
oste
ron
e (
pM
)
POTS
P=0.017P=0.996
POTS
Supine Standing
Ren
in (
(ng
/ml)
/hr)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
P=0.941
Control
P=0.019
Control
Adapted from HI Mustafa et al., Heart Rhythm. 2011;8:422-8.
RAAS SCHEMA IN POTS
AGT ANG I ANG II Aldo
Blood Volume
PRA ACE
ANG (1-7)
AT1R
ACE2
CONCLUSIONS: RAAS IN POTS• Things are screwy
• Unusual RAAS profile in POTS• Low blood volume
• Low plasma renin activity
• Low aldosterone
• More work is needed to understand physiology• Decreased ACE2 activity?
• Elevated ANG II due to less degradation?
• Why are aldosterone levels low?
• Can the kidney not hold onto sodium in POTS?• May explain the need for high sodium diets and low blood volume in POTS
HYPERADRENERGIC POTS:INCREASED SNS NERVE FIRING
NORMAL hPOTS
Hyperadrenergic POTS: decreased NE clearance
Slide courtesy of Alex Nackenoff (Vanderbilt)
A NOREPINEPHRINE SYNAPSE
NET
Slide courtesy of Alex Nackenoff (Vanderbilt)
A NOREPINEPHRINE SYNAPSE (2)
SNSTone
NET
Shannon JR, NEJM 2000; 342:541-9.
ORTHOSTATIC INTOLERANCE AND TACHYCARDIA ASSOCIATED WITH NOREPINEPHRINE-TRANSPORTER DEFICIENCYJohn R Shannon, MD, Nancy L Flattem, BS, Jens Jordan, MD,Giris Jacob, MD, DSc, Bonnie K Black, BSN, Italo Biaggioni, MD,Randy D Blakely, PhD, and David Robertson, MD
REACTION AT VANDERBILT
• Excitement
• The cause of POTS has been found!!!
POTS PATIENTS WITH NET MUTATIONS: 2000-2010•
•
•
•
No other patients had this mutation
We had just about given up hope on NET defects as a cause of POTS . . .
Courtesy of Murray Esler, Baker IDI (Melbourne, Australia)
VARIABLE EXPRESSION OF NET PROTEIN IN POTS
Lambert E et al. Circ Arrhythm Electrophysiol 2008;1:103-109
DECREASED NET PROTEIN EXPRESSION IN SOME POTS PATIENTS
80 kDa
50 kDa
Alpha tubulin
Controls POTS SK-N-BE(2)NET
Cont POTS
Role of antibodies in POTS
1. AChR antibody2. Adrenergic antibodies
Schroeder C et al. NEJM 2005;353:1585-1590
GANGLIONIC ACETYLCHOLINE RECEPTOR AB• Discovered at Mayo Clinic• Steve Vernino & Vanda Lennon
• Loss of function Ab at Autonomic Ganglia
• Prevalence in POTS• Mayo: ~7-14% of POTS patients• Now reportedly lower per Dr P Low (Mayo)
• Vanderbilt: 0% of POTS patients
• Presentation is usually Autonomic Failure• Orthostatic hypotension• Constipation, pupil findings
H Li et al., JAHA 2014; 3(1):e000755.
POTS PATIENT SERUM STIMULATES ADRENERGIC RECEPTORS
P<0.001 P<0.001
P=0.20
Art
eri
ola
r d
iam
ete
r(%
baselin
e)
CTR
L
CTR
L+IC
I
CTR
L+IC
I+PR
AZ
PO
TS
PO
TS
+IC
I
PO
TS
+IC
I+PR
AZ
100
80
60
40
H Li et al., JAHA 2014; 3(1):e000755.
BETA-RECEPTOR ACTIVATION FROM POTS SERA
β2
-AR
med
iate
d
cA
MP
rele
ase P<0.001 P<0.001
150
125
75
100
β 2
AR
-sti
mu
late
d c
AM
P
pro
du
cti
on
(%
baselin
e)
B
CTRL CTRL+ICI POTS POTS+ICI50
P=0.15200
150
100
β 2
AR
-sti
mu
late
d c
AM
P
pro
du
cti
on
(%
baselin
e)
A
CTRL POU PVU50
β1
-AR
med
iate
d
cA
MP
rele
ase P<0.001 P<0.001150
125
75
100
β 1
AR
-sti
mu
late
d c
AM
P
pro
du
cti
on
(%
baselin
e)
D
CTRL CTRL+PROP POTS POTS+PROP50
P=0.13
200
150
100
β 1
AR
-sti
mu
late
d c
AM
P
pro
du
cti
on
(%
baselin
e)
C
CTRL POU PVU50
H Li et al., JAHA 2014; 3(1):e000755.
THE MODEL
How could the Ab contribute to the POTS phenotype?
Upright
Pooling of blood in veins
Slight drop in BP causes baroreceptor activation
Normal α1AR mediated vasoconstriction
Slightly increased heart rate, contractility & cardiac output
Healthy
Upright
Pooling of blood in veins
Slight drop in BP causes baroreceptor activation
α1AR-AAb impaired vasoconstriction
Impaired α1AR mediated vasoconstriction
POTS
Increased drop of BP
Exaggerated baroreceptor activation
Exaggerated sympatho-neural response
Increased neuronal and circulating NE
Hemodynamic manifestations in POTS
Partially blocked vascular α1AR
Compensated BP in POTS
Unblocked cardiac β1AREffect enhanced if β1AR-Aab is present
Marked tachycardia in POTS
HOW?
Section 3
POTS: how to manage?
Investigation and treatment
POTS: INVESTIGATIONS• History and physical examination
• Orthostatic vital signs
• CBC, BMP
• Autonomic reflex testing
• Echocardiogram
• Blood volume assessment
• Exercise capacity assessment
POTS: TREATMENT APPROACHES• Exercise
• Increase blood volume• Oral water• Increase salt (diet vs tablets)• Fludrocortisone• Octreotide• IV saline• Acute DDAVP-H2O
• Hemodynamic agents• Midodrine• Propranolol• Pyridostigmine• Ivabradine (emerging)
• Behavioral therapies
EXERCISE IN POTSHistorically
• “Good thing to do”
• Many patients could not/would not• Excessive fatigue (~days) and intolerance
• Anecdotally, those patients that did exercise did better over time• Cause/effect vs selection bias
Now
• Recent data on effects of exercise training in POTS from Dallas, Vienna, and Mayo . . .
EXERCISE STUDY IN POTS – DESIGN
3 months ofexercise training
Cardiac MRI
45-min 60° Upright Tilt
Screening45-min 60 ° Upright Tilt
Blood Volume Measurement
Maximal Exercise Test
Cardiac MRI
Maximal Exercise Test
Blood Volume Measurement
Rowing machineHandheld
weightsCycling
TreadmillSwimmingRunning
Qi Fu et al., JACC 2010;55:2858-68
EXERCISE IN POTS – BENEFITSShort-term exercise training in POTS
• Increases fitness levels
• Increases blood volume
• Cardiac remodeling
• Normalizes sympathetic activity
• Decreases orthostatic tachycardia
Qi Fu et al., JACC 2010;55:2858-68
EXERCISE IN POTS – HOW TO?• Focus on aerobic activity• Some resistance training focused on thighs
• Must be regular• Every other day (4/week)
• 30min/session 45-60min/session
• NO UPRIGHT EXERCISES• Rowing machines• Recumbent cycles• Swimming
• Takes 4-5 weeks to start seeing benefits
POTS: TREATMENT APPROACHES• Exercise
• Increase blood volume• Oral water• Increase salt (diet vs tablets)• Fludrocortisone• Octreotide• IV saline• Acute DDAVP-H2O
• Hemodynamic agents• Midodrine• Propranolol• Pyridostigmine• Ivabradine (emerging)
• Behavioral therapies
G Jacob et al. Circulation 1997;96:575-580
IV SALINE (1L) ACUTELY DECREASES ORTHOSTATIC TACHYCARDIA . . . A LOT!
PLACEBO SALINE
SBP DBP HR
∆B
P m
mH
g o
r ∆
HR
b
pm
40
30
10
-10
20
0
Before
1 hr
2 hrs
p < 0.009
∆B
P m
mH
g o
r ∆
HR
b
pm
40
30
10
-10
20
0
SBP DBP HR
After
ns
p < 0.009
Before
ST Coffin et al., Heart Rhythm. 2012;9:1484-90
DDAVP+H2O REDUCES STANDING HR
PTim e =0.001
PDrug=0.001
PINT=0.001
DDAVP+H2O Placebo
Heart
Rate
(b
pm
)
Pre 1H 4H
125
120
115
110
105
100
95
90
85
Time Post Dose
2H 3H
POTS: TREATMENT APPROACHES• Exercise
• Increase blood volume• Oral water• Increase salt (diet vs tablets)• Fludrocortisone• Octreotide• IV saline• Acute DDAVP-H2O
• Hemodynamic agents• Midodrine• Propranolol• Pyridostigmine• Ivabradine (emerging)
• Behavioral therapies
Jacob, G. et al. Circulation 1997;96:575-580
MIDODRINE DECREASES ORTHOSTATIC TACHYCARDIA . . . A LITTLE BIT
PLACEBO MIDODRINE
1 hr
2 hrs
Before
∆B
P m
mH
g o
r ∆
HR
b
pm
SBP DBP HR
40
30
10
-10
20
0
1 hr
2 hrs
Before
∆B
P m
mH
g o
r ∆
HR
b
pm
SBP DBP HR
40
30
10
-10
20
0
BETA-BLOCKERS IN POTSPro
• Intuitively appealing• High HR lower it
Con
• Stewart et al. studied IV esmolol and found that it DID NOT improve orthostatic tolerance
• Many patients report “intolerance to beta-blockers”
SR Raj et al. Circulation 2009;120:725-734
PROPRANOLOL 20MG LOWERS ORTHOSTATIC TACHYCARDIA
STANDING HR ORTHOSTATIC INCREASE IN HR
Propranolol Placebo
PDrug <0.001
Time Post Dose
0
10
20
30
40
Ch
an
ge in
Heart
R
ate
(b
pm
)
Pre 1H 4H2H 3HHeart
Rate
(b
pm
)
Pre 1H 4H70
80
90
100
110
120
130
Time Post Dose
2H 3H
PropranololPDrug <0.001Pint <0.001
Placebo
SR Raj et al. Circulation 2009;120:725-734
PROPRANOLOL IMPROVES SYMPTOMS . . .
DDAVP+H2O Placebo
PINT=0.04
Pre 2H 4H
Sym
pto
ms (
au
)
Time Post Dose
26
24
22
20
18
16
14
12
SR Raj et al. Circulation 2009;120:725-734
. . . BUT LESS IS MORE
P =0.041Wilcoxon
Propranolol 20mg Propranolol 80mg
-15
-10
-5
0∆
Sym
pto
ms S
core
(au
)
ACETYLCHOLINESTERASE INHIBITION• Pyridostigmine
• Peripheral AChEI
• Increases availability of synaptic ACh
• Ganglionic Nicotinic Receptor• SNS and PNS
• Postganglionic Muscarinic Receptor• PNS
• Might decrease tachycardia in POTS
SR Raj et al., Circulation 2005;111:2734-2740
ACETYLCHOLINESTERASE INHIBITION (2)
STANDING HEART RATE SYMPTOMS
Time Post Dose
Heart
Rate
(b
pm
)
Pre 2H 4H
135
130
125
120
115
110
105
100
95
90
P=0.160
Placebo
P=0.001
Pyridostigmine
P=0.025
PlaceboPyridostigmine
Ch
an
ge in
Sym
pto
m
Score
(au
)
-15
-10
-5
0
5
P<0.001
P<0.001
EA Green et al., JAHA 2013;2:e000395
NOREPINEPHRINE TRANSPORTER INHIBITION
STANDING SEATED
PInt =0.029
B
Time Post Dose
70
75
80
85
90
95
100
Heart
Rate
(b
pm
)
Pre 1H 4H2H 3H
PlaceboAtomoxetine
PInt <0.001
A
Time Post Dose
90
100
110
120
130
Heart
Rate
(b
pm
)
Pre 1H 4H2H 3H
PlaceboAtomoxetine
EA Green et al., JAHA 2013;2:e000395
NOREPINEPHRINE TRANSPORTER INHIBITION (2)
ORTHOSTATIC CHANGE SYMPTOMS: 0 TO 2H
PInt =0.001
Time Post Dose
Pre 1H 4H15
20
25
30
35
40
C
∆H
eart
Rate
(b
pm
)
2H 3H
P =0.028
Atomoxetine
Placebo
6
∆S
ym
pto
ms S
core
(au
)
4
2
0
-2
-4
-6
-8
PlaceboAtomoxetine
POTS: TREATMENT APPROACHES• Exercise
• Increase blood volume• Oral water• Increase salt (diet vs tablets)• Fludrocortisone• Octreotide• IV saline• Acute DDAVP-H2O
• Hemodynamic agents• Midodrine• Propranolol• Pyridostigmine• Ivabradine (emerging)
• Behavioral therapies
What type of POTS do I have?
Challenges:
1. Overlapping subsets2. Lost in translation
Hyperadrenergic POTS Neuropathic POTS
Hypovolemic POTS
WHAT TYPE OF POTS DO I HAVE?
WHAT TYPE OF POTS DO I HAVE?
Hyperadrenergic POTS Neuropathic POTS
Hypovolemic POTS
LOST IN TRANSLATION
Not my M-I-L
PROGNOSIS OF POTS
“Prediction is very difficult, especially about the future.”
Niels Bohr (1885-1962); Nobel Prize (Physics) 1922
POTS: TAKE HOME MESSAGESPOTS
• Chronic disorder associated with significant disability
• Syndrome . . . not one disease• Multiple pathophysiologies
Treatment
• Exercise
• Volume expansion
• Heart rate control
• Manage the “living with a chronic illness”
QUESTIONS?