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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

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

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

WHAT is POTS?

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

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

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

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

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)

POTS – Who is affected?

n  Prevalence ½ million in USA n  Female (~80-85%) n  Typically aged 13-50 years

n  Significant functional disability

Quality of Life in POTS

Kanika Bagai

Health Related Quality of Life (SF-36) – Chronic Illnesses

Physical Mental0

25

50

75

100 Back PainESRD

SF36 Sub-Scores

Scor

eDialysis

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

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

WHY do they have POTS?

… ‘final common pathway’ of hundreds of genetic and acquired autonomic and cardiovascular entities

- David Robertson

David Robertson

Pathophysiology of POTS – The Challenge

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)

Pathophysiology of POTS

Satish

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…

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

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

Leg Blood Flow May Identify Different Subpopulations of POTS

Julian Stewart

Stewart J M et al. AJP Heart Circ Physiol 2003;285:H2749-H2756

Blood Volume & Renin-Angiotensin-Aldosterone System in POTS

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

(%)

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

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.

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.

Hyperadrenergic POTS – Increased SNS Nerve Firing

Normal hPOTS

Hyperadrenergic POTS – Decreased NE Clearance

A Norepinephrine Synapse

NET

Slide courtesy of Alex Nackenoff

(Vanderbilt)

A Norepinephrine Synapse

NET

Slide courtesy of Alex Nackenoff

(Vanderbilt)

SNS Tone

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

Reaction at Vanderbilt

n  Excitement

n  The cause of POTS has been found!!!

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…

Variable Expression of NET Protein in POTS

Courtesy of Murray Esler, Baker IDI (Melbourne, Australia)

Lambert E et al. Circ Arrhythm Electrophysiol 2008;1:103-109

Decreased NET Protein Expression in some POTS Patients

Role of Antibodies in POTS

1.  AChR Antibody 2.  Adrenergic Antibodies

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

POTS Patient serum stimulates adrenergic receptors

H Li et al., JAHA 2014; 3(1):e000755.

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.

The Model

How could the Ab contribute to the POTS phenotype?

H Li et al., JAHA 2014; 3(1):e000755.

POTS – HOW to Manage?

Investigation & Treatment

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

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

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…

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

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

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

G Jacob et al. Circulation 1997;96:575-580

IV Saline (1L) Acutely Decreases Orthostatic Tachycardia…a LOT!!

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

Jacob, G. et al. Circulation 1997;96:575-580

Midodrine Decreases Orthostatic Tachycardia…a little bit.

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”

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


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

Symptoms

Pre 2H 4H12

14

16

18

20

22

24


PInt =0.04

Time Post Dose

Sym

ptom

s (a

.u.)

Propranolol Improves Symptoms…


Propranolol 20mg Propranolol 80mg

-15

-10

-5

0

P =0.041Wilcoxon

Δ S

ympt

oms

Scor

e (a

.u.)

…but Less is More


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

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)

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

)

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

What Type of POTS Do I Have?

Challenges: 1.  Overlapping Subsets 2.  Lost in Translation

Hyperadrenergic POTS Neuropathic POTS

Hypovolemic POTS

What Type of POTS Do I Have?

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 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”

Questions?