What Might Cause Postural Tachycardia Syndrome (POTS)? &

What Might we Learn from Research to Benefit Patients?

Satish R Raj MD MSCI FACC FHRSProfessor of Cardiac Sciences

Libin Cardiovascular Institute of AlbertaAdjunct Associate Professor of MedicineVanderbilt University Medicine Center

Heart Rhythm Congress, Birmingham, UKOctober 2018

POTS is the‘final common pathway’of hundreds of genetic and acquired

autonomic and cardiovascular entities- David Robertson

David Robertson

What Causes POTS?

Pathophysiology of POTS

Satish

Multiple Pathophysiologies in POTS

• Mast Cell Activation

• Partial Autonomic Neuropathy

• Leg Blood Flow Abnormalities

• Hypovolemia

• Hyperadrenergic

– Increased Release

– Decreased Clearance

• Antibodies are Evil…

Blood Volume & Renin-Angiotensin-

Aldosterone System in POTS

Blood Volume in POTS patients

Raj SR et al. Circulation 2005;111:1574-1582

POTS Patients are Hypovolemic

HR

cha

nge

(bpm

)

Before Saline After Saline0

10

20

30

40

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

IV Saline Decreases HR in POTS

Water and Salt Intake: Common Advice

• Increase salt intake

– Up to 10g/day

– Dietary if possible

– Tablets as needed

• NaCl 1gm tablets

• Salt Stick 250mg buffered tablets

• Increase fluid intake

– 2-3 Liters (8-12 cups) per day

“In God we Trust; All others must bring data.”

- Unknown

Dietary Salt in POTS: Study Design

Low Na+ Diet (LS)

(10mEq/day)

High Na+ Diet (HS)

(300mEq/day)

Low Na+ Diet (LS)

(10mEq/day)

R

ScreeningH&PPlasma Volume

6 day diet 6 day diet//

POTS/

Controls

(HC)

Endpoints: • plasma volume• norepinephrine levels • orthostatic vital signs

High Na+ Diet (HS)

(300mEq/day)

Dietary Salt in POTS: Demographics

POTS(n=14) Controls(n=13) P Value

Age, years 35±2 31±2 0.98

BMI, kg/m2 23±1 24±1 0.577

Na, mEq/l 140±0.29 138±0.42 0.002*

K, mEq/l 3.80±0.07 3.95±0.07 0.082

Cl, mEq/l 107±0.55 106±0.43 0.141

Glucose, mg/dl 87.8±5.38 82.2±2.94 0.512

BUN, mg/dl 10.8±0.73 11.1±0.87 0.883

Cr, mg/dl 0.74±0.02 0.74±0.03 0.789

Hematocrit, % 39±0.76 40±0.45 0.17

Hemoglobin, g/dl 13.1±0.25 13.3±0.15 0.511

Carbon Monoxide-technique Blood Volume

Total blood volume, ml 5139±283 5804±237 0.031*

Red blood cell volume, ml 1951±115 2133±77 0.031*

Plasma volume, ml 3188±174 3671±167 0.02*

High salt diet normalized plasma volume in POTS

HS= high salt dietLS= low salt diet

High salt diet decreased orthostatic tachycardia

High salt diet decreases plasma NE in POTS

Dietary Salt in POTS: Summary• In POTS patients, a HIGH SALT DIET

– Increases plasma volume

– Decreases standing plasma norepinephrine

– Decreases orthostatic tachycardia

• HOWEVER, this did not normalize POTS patients

• POTS patients on a HIGH SALT DIET physiologically resemble Healthy subjects on a LOW SALT DIET

Hyperadrenergic POTS – Decreased NE Clearance

Shannon JR, NEJM 2000; 342:541-9.

Muscle Sympathetic Nerve Activity and Plasma NE

Shannon JR, NEJM 2000; 342:541-9.

Electrochemical Dissociation%

of

Su

pin

e V

alu

e

MSNA [NE] MSNA [NE]0

100

200

300

400

500

Supine

Upright

Normal Patient

Shannon JR, NEJM 2000; 342:541-9.

.

P

P P P

P

S-S

P

V6 9 I

T9 9 I

V2 4 5 I

V4 4 9 I

G4 7 8 S

A4 5 7 PN292T

V356L

A369P N375S

K463R

F528C

Y548H

NL A457P NL A457P

Heart Rate in A457P (NET KO) vs.

Normal Subjects

Orthostatic Tachycardia in Affected Family

Members but not Unaffected Members

Shannon JR, NEJM 2000; 342:541-9.

A Norepinephrine Synapse

NET

Slide courtesy of

Alex Nackenoff

(Vanderbilt)

A Norepinephrine Synapse

NET

Slide courtesy of

Alex Nackenoff

(Vanderbilt)

SNS

Tone

Norepinephrine Transporter Inhibition in POTS

Standing

Pre 1H 2H 3H 4H90

100

110

120

130 Atomoxetine Placebo

PInt <0.001

A

Time Post Dose

Heart

Rate

(b

pm

)

Seated

Pre 1H 2H 3H 4H70

75

80

85

90

95

100

PInt =0.029

B

PlaceboAtomoxetine

Time Post Dose

Heart

Rate

(b

pm

)

EA Green et al., JAHA 2014; 2(5):e000395.

Norepinephrine Transporter Inhibition in POTS

Orthostatic Change

Pre 1H 2H 3H 4H15

20

25

30

35

40 Atomoxetine Placebo

PInt =0.001

C

Time Post Dose

H

eart

Rate

(b

pm

)

Symptoms: 0 to 2h

Atomoxetine Placebo

-8

-6

-4

-2

0

2

4

6

P =0.028

Sym

pto

ms S

co

re (

a.u

.)

EA Green et al., JAHA 2014; 2(5):e000395.

Role of Adrenergic Autoantibodies in POTS

POTS Patient serum stimulates adrenergic receptors

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

POTS Adrenergic Ab - Summary

• POTS IgG in vitro has:

– Alpha-1 Partial Agonist

– Beta-1 Agonist

– Beta-2 Agonist

• This has now been repeated in a different patient cohort

• Do these antibodies have activity in vivo?

– Ongoing Study; Enrollment now open

POTS – Take Home Messages• Research in POTS

– Helps us to understand WHAT IS

WRONG

– Sometimes leads to RATIONAL

TREATMENTS

• Treatment

– High Salt Diet can make things better

– NET inhibitors can make things worse

– Autoantibodies MAY be bad for you

Questions?