postural tachycardia syndrome (pots) what? why? how? satish r raj md msci facc fhrs frcpc associate...

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?