effects of eecp on endothelial function
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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)
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