Effects of EECP on Endothelial Function

barsness.gregory@mayo.edu

Gregory W. Barsness, MD, FACC, FAHA, FSCAIConsultant, Internal Medicine & Cardiology and Radiology

Director, Mayo Clinic EECP LaboratoryDirector, Mayo Clinic Cardiac Intensive Care Unit

Mayo Clinic College of MedicineRochester, MN, USA

Ischemic Conditioning, Endothelial Function and Enhanced External Counterpulsation:

From Research Studies to Patient Care Dallas, TX, November 17, 2013

NOPGI2

ET-1AngII

Normal Endothelial Function

VasodilationAtheroprotective

NO Function

VasodilatoryAntithromboticAntiproliferative

Anti-inflammatory

“Endothelial Balance”

NOPGI2

ET-1AngII

Normal Endothelial Function

VasodilationAtheroprotective

“Endothelial Balance”

NOPGI2 ET-1

AngII

Endothelial Dysfunction

VasoconstrictionAtherogenic

↓Endothelial repairDepletion of EPCs

Endothelial DysfunctionRelationship to Risk Factors

Vita et al: Circ 81:491, 1990

-30-25-20-15-10-505

1015

0 1 2 3 4 5 6

Slope of Ach dose response

relationship (% diameter change/log

Ach)

Risk factors (no.)

r=-0.73P<0.0001

0

100

200

300

400

0

50

100

150

200

250

300

350

CTL AC1 AC2 AC3 PAPA

P<0.01

P<0.005

NSExercise thalliumNormalAbnormal

Coronaryblood flowresponse

(%)

Zeiher, Circulation 1995;91:2345-52.

Endothelial Dysfunction and Ischemia

Car

diac

dea

th/M

I/ re

vasc

/C h

osp

(%)

Years from EndoPAT studyL_RHI <0.4 129 109 100 83 69 56 36 25L_RHI 0.4 140 123 115 104 86 66 55 44

Normalendothelial

function

Cardiac Events in Patients with Abnormal Endothelial Function with EndoPAT

Rubinshtein and Lerman, Euro Heart J 2010

Endothelial Dysfunction

Shear Stress is Atheroprotective

Traub and Berk, ArterioThromb Vasc Biol 18:677, 1998

Pro-growth

Prothrombotic Promigration

Pro-apoptosis

Low mean shear

Ang IIPDGFEndothelin-1

Endothelium

Smoothmuscle

MCP-1VCAM-1

Atherosclerotic lesion

Antigrowth

Antithrombotic Antimigration

Pro-survival

NOTGF

Endothelium

Smoothmuscle

NO

NOPGI2

tPAThrombomodulin

Shear stress

External CounterpulsationSuggested Mechanisms of Action

Clinical Benefit

Neovascularization Remote Preconditioning Endothelial Function

Peripheral Effects Passive Exercise? Placebo Effect

?

? ?

?

?

?

In aorta (like IABP)• Improved retrograde

diastolic and enhanced antegrade systolic flow

Improved flow demonstrated in

• Renal arteries• Carotid arteries• Internal mammary

arteries• Coronary arteries

Doppler Ultrasound of Descending Aorta C

ontr

olEC

P

Shear Stress Increases with EECP13 Hypercholesterolemic Pigs

Pre-EECP During EECP0

10

20

30

40

50

60

70

Shea

r Str

ess

(dyn

es/c

m2)

Zhang et al, Circulation 2007

Vascular Effects of EECP Shear Stress

Improvement of Vascular Health and Gene Expression with EECP

0

20

40

60

80

100

120

140

Control(7 Pigs) CHOL(11 Pigs) CHOL+EECP(17 Pigs)

Perc

ent Intima/Media Thickness Ratio

eNOS Level (% of Control)

Zhang et al, Circulation 2007

Dose-Related NO Increase

0

50

100

150

200

250

Pre-EECP

1-hr

12-hr

24-hr

Post-EECP

1-Month

3-Month

Endothelin-1 (pg/L)Nitric Oxide (mg/L)ET-1/NO Ratio

2.5

2.0

1.5

1.0

0.5

**

P<0.01

* ** *

36 hours of ECP in 13 patientsAhktar et al, AJC 2006

0

20

40

60

80

100

120

140

Controls (n=20) CAD (n=17)

Ang

iote

nsin

II (p

g/m

l)

BaselinePost EECP (36 hours)

Shear Effect of EECP Plasma Angiotensin II Levels

Lawson et al, Eur Heart J 2001;22(Abstr Suppl):538

*

* †

* p < 0.05 vs controls; † p <0.05 vs CAD baseline

Peripheral Arterial Tonometry (PAT)

Reactive Hyperemia-PAT ProtocolCuff inflation 60 mm > SBP

Cuff deflation

10 minutes 5 minutes 10 minutes

Occlusion

RH-PAT in Patients with Normal and Abnormal Coronary Endothelial Function

0

0.5

1

1.5

2

2.5

Normal CEF (n=26) Abnormal CEF (n=19)

RH-P

AT i

ndex

(1

min

ute)

*p < 0.001

1.8

1.2

PAT Reactive Hyperemia

0

0.5

1

1.5

2

2.5

Day1 Day17 Day35

RH-P

AT in

dex

(1 m

inut

e)

Pre-EECP Post-EECP

p<0.001 p=0.006

Bonetti, Barsness et al, JACC 2003

1.2

EECP Effect on Endothelial Function

1.04 1.05 1.04

1.29

0

0.5

1

1.5

Day 1 Day 17 Day 35 1-monthfollow-up

RH-P

AT in

dex

** p < 0.05 vs. days 1, 17, and 35

Pre-EECP

Bonetti, Barsness et al, JACC 2003

Clinical Benefit and RH-PAT Index CCS Angina Class

1.02 1.071.33

1.17

0

0.5

1

1.5

2

CCS improvement No CCS improvement

RH

-PA

T in

dex *

Day 1 1-month follow-up

* p < 0.05 vs. day 1

Bonetti, Barsness et al, JACC 2003

Clinical Benefit and RH-PAT index

Duke Activity Status Index (DASI)

1.00 1.141.32 1.24

0

0.5

1

1.5

2

DASI improvement No DASI improvement

RH

-PA

T in

dex

*

Day 1 1-month follow-up

* p < 0.05 vs. day 1

Bonetti, Barsness et al, JACC 2003

Circulating Progenitor Cells After EECPFlow Cytometric Analysis (FACS)

10

20

30

40

50

60

70

80

90

100

0

Cel

l cou

nt/ 1

00µL

Buf

fy C

oat

Baseline Day 17 Day 35(final)

1 month post treatment

Normal CED

CD34+ CD45dim(p=0.028)CD133+ CD45dim (p=0.034)CD34+ CD133+ CD45dim(p=0.019)CD34+ CD45 - VEGFR2+ (p=0.17)

HPCHPCHPCEPC

Boilson, Kiernan, Barsness, IJC 2011

Peak Filling Rate (n=12)

0

1

2

3

4

Before After

End-

Dia

stol

ic V

olum

e/se

cExternal Counterpulsation

LV Diastolic Filling Parameters (RNA)

p<0.01

Time to Peak Filling Rate

0

50

100

150

200

250

Before After

mse

c

p<0.05

Urano et al, JACC 2001

Interventions that Improve Endothelial Function and Clinical Outcome

Lipid-LoweringACE Inhibitors/ARBs

Calcium Channel BlockersN-3 Fatty Acids

Glycemic Control in DiabetesBlood Pressure Lowering

Smoking CessationWeight Reduction

ExercisePDE-5 Inhibitors

EECP

The Bottom Line Optimal medical therapy and risk factor

modification are essential to improve endothelial function and outcome

EECP provides safe, effective, durable symptom relief and is associated with:· Improved QoL and vascular health· Potential pathway to improve prognosis via

plaque modification, vascular function and myocardial performance effects (improved systolic and diastolic functional parameters)