Ischemic Conditioning, Endothelial Function and
Enhanced External Counterpulsation:
From Research Studies to Patient Care
Dallas, TX, November 17, 2013
Effects of EECP on
Endothelial Function
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
barsness.gregory@mayo.edu
“Endothelial Balance”
Normal Endothelial Function
NO
ET-1
PGI2
AngII
Vasodilation
Atheroprotective
NO Function
Vasodilatory
Antithrombotic
Antiproliferative
Anti-inflammatory
“Endothelial Balance”
Normal Endothelial Function Endothelial Dysfunction
NO
ET-1
PGI2
AngII
NO
PGI2
ET-1
AngII
↓Endothelial repair
Depletion of EPCs
Vasodilation
Atheroprotective
Vasoconstriction
Atherogenic
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
Endothelial Dysfunction and 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
Cardiac Events in Patients with Abnormal
Endothelial Function with EndoPAT
Cardiac death/MI/
revasc/C hosp (%)
60
Endothelial
Dysfunction
40
Normal
endothelial
function
20
0
0
1
2
3
4
5
6
7
36
55
25
44
Years from EndoPAT study
L_RHI <0.4
L_RHI 0.4
129
140
109
123
100
115
83
104
69
86
56
66
Rubinshtein and Lerman, Euro Heart J 2010
Shear Stress is Atheroprotective
Shear stress
Antithrombotic
NO
PGI2
tPA
Thrombomodulin
Antimigration
NO
Pro-survival
Endothelium
Antigrowth
Low mean shear
NO
TGF
Prothrombotic
Smooth
muscle
Promigration
MCP-1
VCAM-1
Pro-apoptosis
Endothelium
Pro-growth
Ang II
PDGF
Endothelin-1
Atherosclerotic lesion
Smooth
muscle
Traub and Berk, ArterioThromb Vasc Biol 18:677, 1998
External Counterpulsation
Suggested Mechanisms of Action
Neovascularization Remote Preconditioning Endothelial Function
? ? ?
Clinical Benefit
? ?
Peripheral Effects
?
Passive Exercise?
Placebo Effect
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 Increases with EECP
13 Hypercholesterolemic Pigs
70
Shear Stress (dynes/cm2)
60
50
40
30
20
10
0
Pre-EECP
During EECP
Zhang et al, Circulation 2007
Vascular Effects of EECP
Shear Stress
140
Improvement of Vascular Health and
Gene Expression with EECP
120
Percent
100
Intima/Media Thickness Ratio
eNOS Level (% of Control)
80
60
40
20
0
Control(7 Pigs)
CHOL(11 Pigs)
CHOL+EECP(17 Pigs)
Zhang et al, Circulation 2007
Dose-Related NO Increase
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
Shear Effect of EECP
Plasma Angiotensin II Levels
140
Angiotensin II (pg/ml)
Baseline
120
*
Post EECP (36 hours)
100
*†
80
60
40
20
0
Controls (n=20)
CAD (n=17)
* p < 0.05 vs controls; † p <0.05 vs CAD baseline
Lawson et al, Eur Heart J 2001;22(Abstr Suppl):538
Peripheral Arterial Tonometry (PAT)
Reactive Hyperemia-PAT Protocol
Cuff inflation
60 mm > SBP
10 minutes
5 minutes
Occlusion
Cuff
deflation
10 minutes
RH-PAT in Patients with Normal and
Abnormal Coronary Endothelial Function
RH-PAT index (1 minute)
2.5
*p < 0.001
2
1.5
1.8
1
1.2
0.5
0
Normal CEF (n=26)
Abnormal CEF (n=19)
PAT Reactive Hyperemia
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
* 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
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
External Counterpulsation
LV Diastolic Filling Parameters (RNA)
Time to Peak Filling Rate
4
250
p<0.05
p<0.01
200
3
msec
End-Diastolic Volume/sec
Peak Filling Rate (n=12)
2
1
150
100
50
0
0
Before
After
Before
After
Urano et al, JACC 2001
Interventions that Improve Endothelial
Function and Clinical Outcome
Lipid-Lowering
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
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)