CP1278619-0

Blood Pressure Regulation & the Postural Orthostatic Tachycardia

Syndrome (POTS) Deconditioning, Pseudodeconditioning;

Both or Neither?

Blood Pressure Regulation & the Postural Orthostatic Tachycardia

Syndrome (POTS) Deconditioning, Pseudodeconditioning;

Both or Neither?

Michael J. Joyner, MDMayo Clinic

Rochester, MN

Michael J. Joyner, MDMayo Clinic

Rochester, MN

CP1278619-1

Mayo ClinicMayo Clinic

Mayo ClinicScottsdale

Mayo ClinicJacksonville

Mayo ClinicRochester

CP1278619-2

Mayo ClinicMayo Clinic• Emerged in late

1800’s• Practice, Research,

Education• Med school • Training programs• ~ 53,000 employees• ~ 500 mil$ research

budget

The Needs of the The Needs of the Patient Come First!Patient Come First!

CP1278619-3

MAP=CO x TPRMAP=CO x TPR

Feedback control by BaroreflexesFeedback control by Baroreflexes

CP1278619-4

Arterial Pressure Regulation by Baroreflexes

Arterial Pressure Regulation by Baroreflexes

Peripheralvessels

NE

Heart

Cardiovascularcenter

Baroreceptors

NE

+

+ACH-

CP1278619-5

Integrated Baroreflex ResponseIntegrated Baroreflex Response

CP1278619-6

Baroreflex CurveBaroreflex Curve

www.rrk-berlin.de/fvkweb/nephrology/por1.html

CP1278619-7

Overview of TalkOverview of Talk

• What happens when we stand up?

• Definition of POTS

• Is POTS “Psychogenic”?

• A baroreflex “problem”?

• POTS & deconditioning

the same or different?

• The physiological evidence in “related syndromes”

• Ideas about how this might all fit together

• What should we do next?

• What happens when we stand up?

• Definition of POTS

• Is POTS “Psychogenic”?

• A baroreflex “problem”?

• POTS & deconditioning

the same or different?

• The physiological evidence in “related syndromes”

• Ideas about how this might all fit together

• What should we do next?

CP1278619-8

What Happens When You Stand Up?What Happens When You Stand Up?

CP1278619-9

Definition of POTSDefinition of POTS

• Emerged as a recognized syndrome in the 1990s

• Baseline sinus rhythm with no evidence of cardiac disease

• Sustained HR ↑

30 beats/min with 10 min of tilting

• Light-headedness, weakness, palpitations, blurred vision, breathing difficulties, nausea, or headache developing on standing or tilting and resolving with recumbency.

• No sustained or marked orthostatic hypotension

• No other explanation

• Emerged as a recognized syndrome in the 1990s

• Baseline sinus rhythm with no evidence of cardiac disease

• Sustained HR ↑

30 beats/min with 10 min of tilting

• Light-headedness, weakness, palpitations, blurred vision, breathing difficulties, nausea, or headache developing on standing or tilting and resolving with recumbency.

• No sustained or marked orthostatic hypotension

• No other explanation

CP1278619-10

David Streeten, MB, D PhilDavid Streeten, MB, D Phil• Native of Bloemfontein, South

Africa • Medical degree 1946, the

University of the Witwatersrand in Johannesburg

• Doctorate in pharmacology from Oxford in 1951

• The main concern of his research was hypertension and orthostatic intolerance

• AAS President 1996

• Native of Bloemfontein, South Africa

• Medical degree 1946, the University of the Witwatersrand in Johannesburg

• Doctorate in pharmacology from Oxford in 1951

• The main concern of his research was hypertension and orthostatic intolerance

• AAS President 1996

http://www.upstate.edu/library/history/portraitbiogs.shtml

CP1278619-11

Stand up

Postural OrthostaticTachycardia Syndrome (POTS)

Postural OrthostaticTachycardia Syndrome (POTS)

• Dramatic increase in HR on standing

• Absence of orthostatic hypotension

• Dramatic increase in HR on standing

• Absence of orthostatic hypotension

-120 -60 0 60 120 -120 -60 0 60 120

40

80

120

160

60

80

100

120

140

POTS

AP(mmHg)

HR(beats/min)

Time (sec)

Stand up

Control

SAP

DAP

Time (sec)

CP1278619-12

Is POTS “Psychogenic”?Is POTS “Psychogenic”?

• Unusual presentations• No obvious “cause”

for the symptoms

• Some cross talk with CFS and/or Fibromyalgia etc

• Multiple encounters with the “Medical Industrial Complex”

• Psych drugs by the time they get to an “expert”

• Unusual presentations• No obvious “cause”

for the symptoms

• Some cross talk with CFS and/or Fibromyalgia etc

• Multiple encounters with the “Medical Industrial Complex”

• Psych drugs by the time they get to an “expert”

CP1278619-13

Hypothesis: Anxiety Plays a Key Role in the HR Responses in POTS?

Hypothesis: Anxiety Plays a Key Role in the HR Responses in POTS?

POTS patients• Increased HR during

orthostatic stress is due to anxiety OR

• Increased HR during orthostatic stress is a baroreflex mediated response to inadequate α-adrenergic vasoconstriction

POTS patients• Increased HR during

orthostatic stress is due to anxiety OR

• Increased HR during orthostatic stress is a baroreflex mediated response to inadequate α-adrenergic vasoconstriction

CP1278619-14

Will HR Rise During “Sham”

Venous Pooling?

Will HR Rise During “Sham”

Venous Pooling?

• “Sham”

LBNP (Halliwill

et al JAP, 1998)

• MAST pressure = 5 mmHg (relative to outside the LBNP box)

• Prevents venous pooling

• No sensation of severe pressure on legs

• Subject still feels “sucked”

into box

• “Sham”

LBNP (Halliwill

et al JAP, 1998)

• MAST pressure = 5 mmHg (relative to outside the LBNP box)

• Prevents venous pooling

• No sensation of severe pressure on legs

• Subject still feels “sucked”

into box

CP1278619-15

MethodsMethods

Measurements• Arterial pressure: Finapres• Heart rate: ECG• Forearm blood flow: plethysmography

Measurements• Arterial pressure: Finapres• Heart rate: ECG• Forearm blood flow: plethysmography

Lower Body Negative Pressure (LBNP) withand without Medical Anti-Shock Trouser inflation

Lower Body Negative Pressure (LBNP) withand without Medical Anti-Shock Trouser inflation

CP1278619-16

Individual RecordsIndividual Records

AP(mmHg)

HR(beats/min)

FBF(mL/100 mL/

min)

LBNP box or trouserpressure(mmHg)

-3 0 3 6 9 12

Trouser InflationTrouser InflationTrouser Inflation

12

3

No InflationNo Inflation

Time (min)

50100150

-50

10

50

100

150

LBNP box

-3 0 3 6 9 12

ControlControl POTSPOTS

CP1278619-17

Subject CharacteristicsSubject Characteristics

• N = 14* patients F/M = 12/229 ±

2 yrs, 68 ±

2 kg, 170 ±

2 cm

• Drugs off for 5 ½

lives*• N = 10 healthy controls

• N = 14* patients F/M = 12/229 ±

2 yrs, 68 ±

2 kg, 170 ±

2 cm

• Drugs off for 5 ½

lives*• N = 10 healthy controls

CP1278619-18

Group Responses to Real and Sham LBNPGroup Responses to Real and Sham LBNPControlControl POTSPOTS

Standard LBNPStandard LBNP

LBNP boxMAP

(mmHg)

HR(beats/min)

-3 0 3 6 9 12Time (min)

MAST InflationMAST Inflation Vacuum SoundVacuum Sound

50100150

0-3 0 3 6 9 12 -3 0 3 6 9 12

80

120

40

Time (min) Time (min)

-10 -20 -30 -40 mmHgLBNP

-10 -20 -30 -40 mmHg -10 -20 -30 -40 mmHLBNP LBNP

baseline -10 -20 -30 -40

50100150

0

80120

40

LBNP (mmHg)

MAP(mmHg)

HR(beats/min) 0

baseline -10 -20 -30 -40LBNP (mmHg)

baseline -10 -20 -30 -40LBNP (mmHg)

CP1278619-19

Mental StressRationale

Mental StressRationale

Stroop

colored word test

• Increased HR during orthostatic stress is due to anxiety?

• Test HR response

to non-orthostatic anxiety provoking stress

• Increased HR during orthostatic stress is due to anxiety?

• Test HR response to non-orthostatic anxiety provoking stress

pink red white

CP1278619-20

Responses to Mental StressResponses to Mental Stress

20

40

60

80

100

MAP(mmHg)

HR(beats/min)

40

60

80

100

70

80

90

110

100

-3.5 -1 0 1 2 360

70

80

90

100

Time (min) Mental stress (min)baseline 1 2 3

Mental stressInst

ControlControl POTSPOTS

CP1278619-21

Somatic HypervigilanceSomatic Hypervigilance

Score

ControlControl POTSPOTS

0

10

15

20

25

5

0

10

15

20

25

5

* * *

0.0

1.0

1.5

2.0

0.5

Anxiety sensitivityindex

Body vigilancescale

Catastrophizingscale

CP1278619-22

Physiology “Wins”Physiology “Wins”• HR response only happens with venous

pooling • HR response to mental stress “normal”

in

spite of increased hypervigilance • Why?

DenervationHypovolemiaCNS

• Or, is there a deconditioning element and if so how big?

• HR response only happens with venous pooling

• HR response to mental stress “normal”

in spite of increased hypervigilance

• Why?DenervationHypovolemiaCNS

• Or, is there a deconditioning element and if so how big?

CP1278619-23

Is POTS a Baroreflex “Problem”?Is POTS a Baroreflex “Problem”?

• Same subjects

• Overnight hydration

• Upright and supine exerciseSupine exercise and cardiac filling

• Bolus doses of PE during exercise to raise BP and evoke reflex changes in HR

• Same subjects

• Overnight hydration

• Upright and supine exerciseSupine exercise and cardiac filling

• Bolus doses of PE during exercise to raise BP and evoke reflex changes in HR

CP1278619-24

Same exercise protocol was repeated (no stand test)Same exercise protocol was repeated (no stand test)

SupineSupine

UprightUpright

Exercise ProtocolExercise Protocol

Stand test= PE infusion (μg/kg)

2550

75 W

Exercise

0 7 14 21 min

70 min break70 min break

1.5

2.02.5

3.0

AP & HRCO

CP1278619-25

HR(beats/min)

AP(mmHg)

PP(mmHg)

50

90

Rest 25 50 75Workload (watts)

SupineSupine UprightUpright

SAP

MAP

DAP

80

120

160

*

**

80

120

160

Rest 25 50 75Workload (watts)

70

ControlControlPOTSPOTS

Hemodynamic Responses to ExerciseHemodynamic Responses to Exercise

CP1278619-26

CO(L/min)

SV(mL)

TPR(mmHg/L/min)

Rest 25 50 75Workload (watts)

SupineSupine UprightUpright

6

8

12

80

100

Rest 25 50 75Workload (watts)

ControlControlPOTSPOTS

*

10

120

60

8

12

16

SV Responses in POTSSV Responses in POTS

CP1278619-27

0

200

0

200

AP(mmHg)

AP(mmHg)

1 sec

Upright Exercise at 75WUpright Exercise at 75W

Control

POTS

CP1278619-28

Frequency(%)

5

15

20

0

10

-40 -20 0 20 40

5

15

20

0

10

-40 -20 0 20 40

Distribution of PP (mmHg)

Control POTS

BP More Variable in POTSBP More Variable in POTS

CP1278619-29

HR(beats/min)

HR(beats/min)

SAP (mmHg)SAP (mmHg)

ControlControl POTSPOTS

20

60

100

140

100 140 180 220

50W

75W

25W

Rest60

100

140

180

100 140 180 220

50W

75W

25W

Rest

Baroreflex Control of HRBaroreflex Control of HR

CP1278619-30

-1.8

-1.2

-0.6

0

Baroflexsensitivity(beats/min/

mmHg)

Baroflexsensitivity(beats/min/

mmHg)

4040 8080 120120 160160

SupineSupine UprightUpright

Heart RateHeart Rate

ControlControl POTSPOTS

4040 8080 120120 160160

Baroreflex Control: Corrected for HRBaroreflex Control: Corrected for HR

CP1278619-31

Δ

HR,upright —

supine

(beats/min)

Δ

HR,upright —

supine(beats/min)

RestRest 50W50W

Δ

SV, upright —

supine (mL)Δ

SV, upright —

supine (mL)

ControlControl POTSPOTS

-10

0

10

20

30

40

50

-80 -60 -40 -20 00

10

20

30

40

50

-80 -60 -40 -20 0

R2= 0.35 R2= 0.60

Change in SV vs

HRChange in SV vs

HR

CP1278619-32

Exercise Studies Physiology Wins Again

Exercise Studies Physiology Wins Again

• Baroreflex control of HR is not fundamentally different

• Similar responses while supine

• Smaller SV while upright

• Responses are similar when SV is considered: cardiopulmonary interactions

• Small SV is a “hallmark”

of deconditioning

• Baroreflex control of HR is not fundamentally different

• Similar responses while supine

• Smaller SV while upright

• Responses are similar when SV is considered: cardiopulmonary interactions

• Small SV is a “hallmark”

of deconditioning

CP1278619-33

Spaceflight & Regulation of MSNA What Does It Tell Us About POTS?

Spaceflight & Regulation of MSNA What Does It Tell Us About POTS?

• Cardiac atrophy

• Smaller stroke volume

• Reduced blood volume

• Can be simulated by bed-rest deconditioning

• Cardiac atrophy

• Smaller stroke volume

• Reduced blood volume

• Can be simulated by bed-rest deconditioning

CP1278619-34

40

50

60

70

80

90

100

POTS Like Responses to Tilt After Spaceflight N=5

POTS Like Responses to Tilt After Spaceflight N=5

Levine et al J Phys 2002

Heart rate(beats/min-1)

Supine Tilt5

Tilt10

Supine Tilt5

Tilt10

Supine Tilt5

Tilt10

~72 days ~23 daysLanding dayLanding dayPreflightPreflight

* *

CP1278619-35

Levine et al J Phys 2002

MSNA Responses After SpaceflightMSNA Responses After Spaceflight

Musclesympathetic

nerveactivity

Supine

60°

upright tilt

Landing dayLanding dayPreflightPreflight

TimeAstronaut 3

0 10 20 30 40 0 10 20 30 40

CP1278619-36

0

20

40

60

25 50 75 100 125 150

Ventricular Volume & MSNAVentricular Volume & MSNA

Levine et al J Phys 2002

Musclesympathetic

nerveactivity

(bursts/min-1)

PreflightLanding dayPreflightLanding day

Stroke volume (mL)

*

*

CP1278619-37

ΔH

R (b

pm)

ΔH

R (b

pm)

MSNA Responses to 45* HUT in POTS n=9MSNA Responses to 45* HUT in POTS n=9

Swift et al 2005

BaselineBaseline

30 degrees30 degrees

45 degrees45 degrees

Control 20 sControl 20 s POTS 20 sPOTS 20 s

MSN

A (%

of b

asel

ine)

MSN

A (%

of b

asel

ine)

ΔD

BP

(mm

Hg)

ΔD

BP

(mm

Hg)

0

100

200

300

0

10

20

30

0

5

10

15

20

25*P=0.03

P=0.10

*P=0.02

P=0.03P=0.66

P=0.60

45°30° 45°30° 45°30°

ControlControl POTSPOTS

CP1278619-38

010203040506070

010203040506070

MSNA Responses to Nitroprusside

in POTS

MSNA Responses to Nitroprusside

in POTS

Bonyhay

and Freeman 2004

Burstfrequency

(bursts/min)

Burstfrequency

(bursts/min)

0102030405060

NPBaseline

POTSPOTS ControlControlΔ

=20.4±7.5Δ

=20.4±7.5 Δ

=12.1±4.1Δ

=12.1±4.1

Δ

=21.8±8.4Δ

=21.8±8.4 Δ

=14.4±5.2Δ

=14.4±5.20

102030405060

Burstincidence(bursts/

100 heart beats)

Burstincidence(bursts/

100 heart beats)

NPBaseline

CP1278619-39

Further Evidence from the Dallas Group

Further Evidence from the Dallas Group

CP1278619-40

0 20 40 60 80 100 120 1400

10

20

30

40

50

60

70

80

0 20 40 60 80 100 120 140

r = 0.87 ±

0.15r = 0.96 ±

0.05

MSNA and SV Relationships in POTSMSNA and SV Relationships in POTS

MSNA(bursts/min)

ControlsControlsPOTSPOTS

Stroke volume (mL)

CP1278619-41

0 20 40 60 80

Linear Correlation Between Total Peripheral Resistance and MSNA During Orthostasis

in POTS Patients And Controls

Linear Correlation Between Total Peripheral Resistance and MSNA During Orthostasis

in POTS Patients And Controls

500

1000

1500

2000

2500

3000

3500

4000

0 20 40 60 80

r = 0.81 ±

0.19r = 0.89 ±

0.09

Totalperipheralresistance(dyne·sec·

cm-5)

ControlsControlsPOTSPOTS

Stroke volume (mL)

CP1278619-42

SV and HR in POTSSV and HR in POTS

POTSControls

Mean±SD

Supine

30°

tilt

60°

tilt

60°

tilt5 min

10 minSupine

30°

tilt

60°

tilt

60°

tilt5 min

10 minSupine

30°

tilt

60°

tilt

60°

tilt5 min

10 minSupine

30°

tilt

60°

tilt

60°

tilt5 min

10 min

0

20

40

60

80

100

120

140

160

0

20

40

60

80

100

120

Heart rate (beats/min)Heart rate (beats/min)Stroke volume (mL)Stroke volume (mL)Group P=0.005Protocol P<0.001Group X Protocol P=0.015

Group P<0.001Protocol P<0.001Group X Protocol P=0.847

CP1278619-43

LV Mass Increased After 3-Month of Exercise Training in POTS

LV Mass Increased After 3-Month of Exercise Training in POTS

Before

After

Healthy training

training

womenBefore

After

Healthy training

training

women

Left ventricular mass (g)

Left ventricular mass (g)

0

20

40

60

80

100

120

140 12

+40%

CP1278619-44

50

60

70

80

90

100

110

120

50

60

70

80

90

100

110

120

Heart Rate Responses During 10-min Standing Before and After Exercise Training

Heart Rate Responses During 10-min Standing Before and After Exercise Training

1

Heart rate

(bpm)

2

+37+36

+7

+22

Supine Stand 10 min

Supine Stand 10 min

CP1278619-45

POTS Interim Summary

POTS Interim Summary

• Physiological data looks like deconditioning

• Some evidence that training “works”

• Psych data suggests hypervigilance

• Is there a triggering “event”

followed by prolonged inactivity

• Heterogeneous syndrome, what this might not explain

• Physiological data looks like deconditioning

• Some evidence that training “works”

• Psych data suggests hypervigilance

• Is there a triggering “event”

followed by prolonged inactivity

• Heterogeneous syndrome, what this might not explain

CP1278619-46

The Physiological Evidence & “Related Syndromes”

The Physiological Evidence & “Related Syndromes”

Is There a Similar Story for CFS and Fibromyaligia?

Is There a Similar Story for CFS and Fibromyaligia?

CP1278619-47

HR Responses Normal During Exercise in CFS n=31

HR Responses Normal During Exercise in CFS n=31

Wallman et al 2004

Heart rate (bmp)

Heart rate (bmp)

CFSControls

WattsWatts

60

80

100

120

140

160

25 50 75 100 125 150 175

CP1278619-48

Oxygen Uptake Responses Normal During Exercise in CFS

Oxygen Uptake Responses Normal During Exercise in CFS

Wallman et al 2004

Oxygen uptake

(mL·kg·min)

Oxygen uptake

(mL·kg·min)

CFSControls

WattsWatts

0

5

10

15

20

25

30

25 50 75 100 125 150 175

CP1278619-49

Perception of Effort During Exercise Altered

in CFS

Perception of Effort During Exercise Altered

in CFS

Wallman et al 2004

RPERPE

CFSControls

WattsWatts

6

8

10

12

14

16

18

20

25 50 75 100 125 150 175

CP1278619-50

Muscle Metabolism is Normal in CFS NMR Measures of ADP n=19

Muscle Metabolism is Normal in CFS NMR Measures of ADP n=19

• Quad exercise

• Cuffs to limit blood flow

• NMR measures of metabolism

• Doppler measures of flow

• Quad exercise

• Cuffs to limit blood flow

• NMR measures of metabolism

• Doppler measures of flow

McCully et al J Appl Physiol 2003

End exercise

ADP (uM)

End exercise

ADP (uM)

Cuff pressure during recovery (mmHg)Cuff pressure during recovery (mmHg)

Muscle Vmax

(mL/min)

Muscle Vmax

(mL/min)

CFS Controls

0102030405060708090

0 50 60 70 80 90 0

0102030405060708090

0 50 60 70 80 90 0

CP1278619-51

0100200300400500600700800900

1000

-60 0 60 120 180 240 300 360 420

Muscle Blood Flow Not Grossly Abnormal In CFS

Muscle Blood Flow Not Grossly Abnormal In CFS

McCully et al J Appl Physiol 2003

Blood flow

(mL/min)

Blood flow

(mL/min)

SecondsSeconds

Free Flow60 mmHg90 mmHg

A B

CP1278619-52

Does CFS Respond to Training?Does CFS Respond to Training?82 volunteers82 volunteers

68 subject randomized68 subject randomized

14 excluded for14 excluded fornot meeting criterianot meeting criteria

Exercise groupExercise group(n=34)(n=34)

Relaxation/flexibilityRelaxation/flexibilitygroup (n=34)group (n=34)

4 weeks4 weeks’’

baselinebaselinetestingtesting

2 exercise2 exercisesubjects withdrewsubjects withdrew

2 relaxation/flexibility2 relaxation/flexibilitysubjects withdrewsubjects withdrew

12 weeks12 weeks’’

graded exercisegraded exercisewith pacing (n=32)with pacing (n=32)

12 weeks12 weeks’’

relaxation/flexibility relaxation/flexibility (n=29)(n=29)

4 weeks4 weeks’’

postpost--intervention testingintervention testing

CP1278619-53

1.0

1.5

2.0

0.100.15

0.200.25

1000015000200002500030000

Baseline Post-intervention

CFS Responds to TrainingCFS Responds to Training

Wallman et al 2004

Self-rated clinical global impression change scores after

completing treatment

Self-rated clinical global impression change scores after

completing treatmentGraded

Relaxationexercise

flexibilityn=32

n=29Rating

No. (%)

No. (%)

Very much better

5 (16)

2 (7)Much better

14 (44)

10 (34%)A little better

10 (31%)

10 (34%)No change

3 (9%)

6 (21%)A little worse

0

1 (3%)Much worse

0

0Very much worse

0

0

Graded

Relaxationexercise

flexibilityn=32

n=29Rating

No. (%)

No. (%)

Very much better

5 (16)

2 (7)Much better

14 (44)

10 (34%)A little better

10 (31%)

10 (34%)No change

3 (9%)

6 (21%)A little worse

0

1 (3%)Much worse

0

0Very much worse

0

0

Values are number (%) of people choosing each rating

Changes (95% CIs) in selected physicological

variables

Changes (95% CIs) in selected physicological

variables

Pow

erou

tput

(W/k

g)

RPE

/po

wer

Act

ivity

leve

l(k

J/w

eek)

Relaxation/flexibility group (n=29)Relaxation/flexibility group (n=29)Graded exercise group (n=32)Graded exercise group (n=32)

CP1278619-54

CFS Interim Summary

CFS Interim Summary

• Physiological data looks “normal”

• Some evidence that training “works”

• Psych data suggests perception of effort is altered

• Is there a triggering “event”

followed by prolonged inactivity

• Heterogeneous syndrome, what this might not explain

• Physiological data looks “normal”

• Some evidence that training “works”

• Psych data suggests perception of effort is altered

• Is there a triggering “event”

followed by prolonged inactivity

• Heterogeneous syndrome, what this might not explain

CP1278619-55

Same Story For FibromyaligiaSame Story For Fibromyaligia

Richards and Scott 2002

220 offered screening

196 screened• Not fibromyalgia (n=29)• Too mild (n=9)• Fibromyalgia but ineligible (n=22)

Randomized (n=136)

Exercise group (n=69) Relaxation group (n=67)

AdherenceNo of classes attended:

0 111-8

169-16

2317-24

19

AdherenceNo of classes attended:

0 111-8

169-16

2317-24

19

CP1278619-56

Exercise Improves Symptoms in Fibromyalgia

Exercise Improves Symptoms in Fibromyalgia

Mean scores (95% CI) Mean change between groups

(95% CI)TimeRelaxation group n=67

Exercise group n=69 P

Baseline 14.0 (13.4-14.6) 14.4 (13.7-15.1) NA NA

3 months 11.8 (10.9-2.8) 10.6 (9.2-12.0) 1.1 (-0.47-2.6) 0.21

6 months 11.2 (10.0-12.3) 10.2 (8.9-11.5) 1.4 (-0.1-2.8) 0.07

1 year 12.0 (10.8-13.0) 10.2 (8.8-11.6) 2.2 (0.63-3.7) 0.019

CP1278619-57

Summary Thoughts How This Might All Fit Together

Summary Thoughts How This Might All Fit Together

• POTS, CFS and Fibromyalgia defy a clear physiological explanation

• Triggering event

• Perceptual “mismatch”?

• Chronic deconditioning as a sustaining factor?

• “Medicalization”

as a sustaining factor?

• POTS, CFS and Fibromyalgia defy a clear physiological explanation

• Triggering event

• Perceptual “mismatch”?

• Chronic deconditioning as a sustaining factor?

• “Medicalization”

as a sustaining factor?

CP1278619-58

What To Do Next?What To Do Next?

• Exercise based rehab

• Demedicalize

• Perceptual “retraining”

• Continued empathy for the patients with a firm consistent message

• Exercise based rehab

• Demedicalize

• Perceptual “retraining”

• Continued empathy for the patients with a firm consistent message

CP1278619-59

AcknowledgementsAcknowledgementsN Dietz

J Eisenach

N Charkoudian

F Dinenno

W Schrage

S MasukiM Tschakovsky

K Krucker

P Engrav

S Roberts

D Wick

E MartinC Johnson

B Walker

E Snyder

K Engelke

B Wilkins

N NicholsonZ Liu

T Curry

J Halliwill

C Minson

D Proctor

L SokolnikiT Pike

A Reed

M Ceridon

L Berry

T Young

S ShastryR Kraft

M Somanju

A Issa

C Hesse

F Ramirez

P KredietT Pike

B Welch

P Sandroni

B Johnson

S Turner

M JensenJT Shepherd

BG Wallin

PA Low

N Dietz

J Eisenach

N CharkoudianF Dinenno

W Schrage

S Masuki

M Tschakovsky

K Krucker

P EngravS Roberts

D Wick

E Martin

C Johnson

B Walker

E SnyderK Engelke

B Wilkins

N Nicholson

Z Liu

T Curry

J HalliwillC Minson

D Proctor

L Sokolniki

T Pike

A Reed

M CeridonL Berry

T Young

S Shastry

R Kraft

M Somanju

A IssaC Hesse

F Ramirez

P Krediet

T Pike

B Welch

P Sandroni

B Johnson

S Turner

M JensenJT Shepherd

BG Wallin

PA Low

CP1153975-61

CP1278619-60

CP1278619-61

If All You Have is a Hammer… Everything Looks Like a Nail

If All You Have is a Hammer… Everything Looks Like a Nail

Physician Physician PerspectivePerspective•• CardiologyCardiology•• NeurologyNeurology•• PsychPsych

CP1278619-62

If All You Have is a Hammer… Everything Looks Like a Nail

If All You Have is a Hammer… Everything Looks Like a Nail

Physician PerspectivePhysician PerspectiveJoyner & Levine Teams Joyner & Levine Teams interested in exercise; interested in exercise; ““DetrainingDetraining”” usually on usually on the differential the differential

CP1278619-63

0

10

20

30

40

50

60

70

MSNA Responses to HUT in POTSMSNA Responses to HUT in POTS

Supine 30°

tilt

60°

tilt

60°

tilt

5 min 10 min

Supine 30°

tilt

60°

tilt

60°

tilt

5 min 10 min

Group P=0.198Protocol P<0.001Group x Protocol P<0.001

POTSControls

MSNA (bursts/min)

MSNA (bursts/min)

CP1278619-64

POTS Like Responses to 120 Days of HDT n=6POTS Like Responses to 120 Days of HDT n=6

Kamiya

et al Am J Physiol

Regulatory Integrative Comp Physiol

2000

Cha

nges

in M

BP

(mm

Hg)

Cha

nges

in M

BP

(mm

Hg)

Pre-HDBRPre-HDBR HDBR60HDBR60

**

Cha

nges

in to

tal M

SNA

(arb

itrar

y un

its/m

in)

Cha

nges

in to

tal M

SNA

(arb

itrar

y un

its/m

in)

****

Cha

nges

in h

eart

rate

(bea

ts/m

in)

Cha

nges

in h

eart

rate

(bea

ts/m

in)

**

HDBR120HDBR120 Rec-HDBR (n=3)Rec-HDBR (n=3)

-12

-8

-4

0

4

0

1000

2000

3000

4000

5000

0

10

20

30

CP1278619-65

Baroflexsensitivity(beats/min/

mmHg)

Baroflexsensitivity(beats/min/

mmHg)

WorkloadWorkload

SupineSupine UprightUpright

*

*-1.8

-1.2

-0.6

0 RestRest 2525 5050 7575 RestRest 2525 5050 7575

ControlControl POTSPOTS

CP1278619-66

∆

HR(beats/min)

∆

arterialpressure(mmHg)

-20

-10

0

10

20

30

0

10

20

30

40

50

SAP DAP MAP

ContPOTS

P=0.37 P=0.0033 P=0.18

P <0.001