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14th Vietnam National Congress of Cardiology
Da Nang, Vietnam
October 11-14, 2014

Managing Angina and Risk via
Improved Endothelial Function:
The EECP Model
Gregory W. Barsness, MD, FACC, FAHA, FSCAI
Consultant, Internal Medicine & Cardiology and Radiology
Director, Mayo Clinic EECP Laboratory
Director, Mayo Clinic Cardiac Intensive Care Unit

Mayo Clinic College of Medicine
Rochester, MN, USA

Nothing to Disclose Related to this Talk


Endothelial Function
The Importance of Balance
Normal Endothelial Function

NO

ET-1

PGI2

AngII

Vasodilation

Atheroprotective

NO Function
Vasodilatory
Antithrombotic
Antiproliferative
Anti-inflammatory


Endothelial Function
The Importance of Balance
Endothelial Dysfunction

NO
PGI2

ET-1
AngII

↓Endothelial repair
Depletion of EPCs

Vasoconstriction
Atherogenic


Coronary Endothelial Dysfunction
Relationship to Risk Factors
15
10

5
Slope of
0
Ach dose
response
-5
relationship
(% diameter -10
change/log -15
Ach)
-20
-25
-30

r=-0.73
P<0.0001

0

1

2

3

4

5

6

Risk factors (no.)
Vita et al: Circ 81:491, 1990


Coronary Endothelial Dysfunction
Relationship to Ischemia
350
300

Coronary
blood flow
response
(%)

NS

Exercise thallium
Normal
Abnormal

250

400

300

P<0.005

200

200

P<0.01

150
100

100

50
0

0
CTL

AC1

Zeiher, Circulation 1995;91:2345-52.

AC2

AC3

PAPA


Abnormal Peripheral Endothelial Function
Relationship to Cardiac Events
Cardiac death/MI/

revasc/C hosp (%)

60

Endothelial
Dysfunction

40

Normal
Endothelial
Function

20

0
0

1

2

3

4

5

6

7

Years from EndoPAT study
Rubinshtein and Lerman, Euro Heart J 2010


Vulnerability
Smoking

Hypertension

Hypercholesterolemia

New risk
factors

Diabetes

Genomic
predisposition

Endothelial Dysfunction ► The Vulnerable Patient

Dementia

Heart failure

Bonetti et al, ATVB 2003

Stroke

Acute Coronary
syndrome

Sudden death

Naghavi et al, Circulation 2003


Importance of Shear Stress
CTO Revascularization and 7 Mo FollowUp

Shear Stress is Atheroprotective
• Antithrombotic
• Antimigration
• Pro-Survival
Shear Stress is Vasodilatory


ECG-Gated Sequential Diastolic Activation


EECP Enhances Shear Stress Forces
Doppler Ultrasound of Descending Aorta
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


Shear Stress Effect of EECP
Dose-Related NO Increase in Humans
Endothelin-1 (pg/L)
Nitric Oxide (mg/L)
ET-1/NO Ratio

250
200

2.5

*

150

2.0

*
P<0.01

1.5

100

*
50

*

*
th
on
3M

on

th

0.5

1M

EC
P
st
-E

hr
Po

24

-

hr
12
-

r
1h

EE

CP

0

Pr
e-

1.0

*

36 hours of ECP in 13 patients
Ahktar et al, AJC 2006


Reactive Hyperemia-PAT Protocol
Cuff inflation
60 mm > SBP
10 minutes

5 minutes

Occlusion

Cuff

deflation
10 minutes


Quantitation of RH-PAT (RH-PAT index)

Post-occlusion PAT-amplitude

RH-PAT index =
Pre-occlusion PAT-amplitude


EECP Effect on Endothelial Function
RH-PAT During Treatment
p=0.006

RH-PAT index (1 minute)

2.5
p<0.001

2
1.5

1.2
1
0.5
0
Day1

Day17

Pre-EECP
Bonetti, Barsness et al, JACC 2003

Post-EECP

Day35


EECP Effect on Endothelial Function
RH-PAT 1 Month Following Treatment
* p < 0.05 vs. days 1, 17, and 35
1.5

*

RH-PAT index

1.29
1

1.04

1.05

1.04

Day 1

Day 17

Day 35

0.5

0

Pre-EECP
Bonetti, Barsness et al, JACC 2003

1-month
follow-up


Clinical Benefit and RH-PAT Index
CCS Angina Class
* p < 0.05 vs. day 1

RH-PAT index

2

*

1.5
1

1.33
1.02

1.07

1.17

0.5
0
CCS improvement
Day 1

Bonetti, Barsness et al, JACC 2003

No CCS improvement
1-month follow-up


Clinical Benefit and RH-PAT index
Duke Activity Status Index (DASI)
* p < 0.05 vs. day 1

RH-PAT index

2

*

1.5
1.32

1
1.00

1.14

1.24

0.5
0
DASI improvement
Day 1

Bonetti, Barsness et al, JACC 2003

No DASI improvement
1-month follow-up


Relation Between the Number of Endothelial Progenitor Cells
and Endothelial Function
Endothelial progenitor cells
(colony-forming units)
r=-0.59
P<0.001

Change in brachial reactivity (%)
Hill et al: NEJM 348(7):597, 2003

CP1099981-3


Circulating Progenitor Cells After EECP
Flow Cytometric Analysis (FACS)
100

HPC
HPC
HPC
EPC

Cell count/ 100µL Buffy Coat

90

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

80
70
60
50
40

30
20
10
0
Normal

CED

Baseline

Boilson, Kiernan, Barsness, IJC 2011

Day 17

Day 35
(final)

1 month post
treatment


Where do we go from here?


Persistent Endothelial Dysfunction
is Associated with CV Events
Cumulative eventfree probability

1.0

Improved FMD

0.8

Persistently impaired FMD

0.6
0.4
0.2
P<0.01

0.0
0

10

20

30

Months after enrollment
Kitta Y et al: J Am Coll Cardiol 53:323, 2009

CP1343701-4


Interventions that Improve Endothelial
Function and Clinical Outcome
Statins/Low Fat Diet
ACE Inhibitors/ARBs

Calcium Channel Blockers
N-3 Fatty Acids
Glycemic Control in Diabetes
Blood Pressure Lowering
Smoking Cessation
Weight Reduction
Exercise
PDE-5 Inhibitors
Aspirin

EECP


The Bottom Line
 Optimal

medical therapy and risk factor
modification are essential to improve
endothelial function and outcome
 Exercise and EECP provide safe,
effective, durable symptom relief:
 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)



Mayo Clinic

Rochester, MN, USA

CP1124540-1