EECP Randomized Study - NO Production
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Transcript EECP Randomized Study - NO Production
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
[email protected]
“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)