International Journal of Cardiology 166 (2013) 38–43

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Review

Vasculoprotective properties of enhanced external counterpulsation for coronary

artery disease: Beyond the hemodynamics
Da-ya Yang, Gui-fu Wu ⁎
Division of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, China
The Key Laboratory on Assisted Circulation, The Ministry of Health, China

a r t i c l e i n f o a b s t r a c t

Article history: A growing pool of evidence has shown that enhanced external counterpulsation (EECP) is a non-invasive,
Received 29 October 2011 safe, low-cost, and highly beneficial therapy for patients with coronary artery disease. However, the exact
Received in revised form 22 February 2012 mechanisms of benefit exerted by EECP therapy remain only partially understood. The favorable hemody-
Accepted 1 April 2012
namic effects of EECP were previously considered as the primary mechanism of action. Nevertheless, recent
Available online 4 May 2012
advances have shed light on the shear stress-increasing effects of EECP which are vasculoprotective and anti-
Keywords:
atherosclerotic. EECP-induced endothelial shear stress increase may lead to improvement in endothelial
Atherosclerosis function and morphology, attenuation of oxidative stress and inflammation, and promotion of angiogenesis
Coronary artery disease and vasculogenesis. This review summarizes evidence of the potential mechanisms contributing to the im-
Enhanced external counterpulsation mediate and long-term benefits of EECP, from the perspective of its shear stress-increasing effects.
Hemodynamics © 2012 Elsevier Ireland Ltd. All rights reserved.
Shear stress

1. Introduction in the heterogeneous patient population seen in clinical practice. Fur-

Enhanced External Counterpulsation (EECP) is a non-invasive pneu-
matic technique that utilizes rapid electrocardiogram-gated sequential
inflation of cuffs wrapped around the calves, thighs, and buttocks at
supra-systolic pressures during diastole, followed by simultaneous de-
flation during systole. The hemodynamic effects of EECP, primarily dia-
stolic augmentation and systolic unloading, in addition to increased
venous return, result in an increase in cardiac output [1] as well as an
increase in blood flow to various vascular beds, including the coronary
arteries [2].
The positive clinical effects of EECP, documented by several prelim-
inary small trials, included reduction of angina [3–9] and nitrate use
[3,5,6], increased exercise tolerance [4,5,8,10–12], favorable psycho-
social effects and improved quality of life [13,14], as well as prolonga-
tion of the time to exercise-induced ST-segment depression [11,12],
and an accompanying resolution of myocardial perfusion defects
[3–6,8,10–12]. In 1999, Arora et al. reported the clinical benefits of
EECP with the results of the first randomized, double-blinded, sham-
controlled Multicenter Study of Enhanced External Counterpulsation
(MUST-EECP) [15], with a sub-study showing a significant improve-
ment in quality of life parameters sustained in up to 12 months of
follow-up [16]. In the International EECP Patient Registry (IEPR) [17]
and the EECP Clinical Consortium [18], these benefits were confirmed
⁎ Corresponding author at: Division of Cardiology, The First Affiliated Hospital, Sun
Yat-sen University, 58 Zhongshan Rd II, Guangzhou, 510080, China. Tel.: + 86 20
87330202; fax: + 86 20 87330396.
E-mail address: eecpchina@yahoo.com.cn (G. Wu).
thermore, patients with a favorable initial clinical response enjoyed a
sustained benefit from EECP up to 5 years, as indicated by the follow-
up data [3,17,19,20]. Currently, EECP therapy is recommended by the
American Heart Association [21] as well as the Chinese Medical Associ-
ation [22] as a Class IIb intervention for treatment of refractory angina
pectoris (RAP); while the European Society of Cardiology views it as
an interesting modality available for the treatment of RAP and calls for
more clinical trials to further define its role in treating RAP [23].
Although the body of evidence continues to grow, the exact mech-
anisms by which EECP exerts its significant and sustained anti-anginal
and vasoprotective effects remain poorly understood. Nevertheless,
recent advances in vascular biology have yielded insights into how
EECP brings about the clinically favorable effects mentioned above.
Most studies have targeted the vascular endothelial cell and demon-
strated shear stress-related favorable responses to EECP in atheroscle-
rotic diseases. By reviewing currently available literature, this article
summarizes the potential mechanisms supposedly responsible for
the immediate and long-term benefits of EECP, in terms of the classic
hemodynamic and the shear stress-related effects of EECP, with high-
lights of the latter (Fig. 1).
2. The hemodynamic effects of EECP
The technique of EECP involves pneumatic inflation of three pairs of
cuffs compressing the calves, thighs and buttocks in a sequential distal-
to-proximal manner in early diastole, followed by simultaneous defla-
tion just before the following systole. Similar to the effects of Intraaortic
Balloon Pumping (IABP), the diastolic compression significantly raises

0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2012.04.003
 D. Yang, G. Wu / International Journal of Cardiology 166 (2013) 38–43
Fig. 1. Currently understood mechanisms of EECP.
diastolic pressure (diastolic augmentation), thereby creating a strong
retrograde flow (counterpulse) of freshly oxygenated blood to the heart
and coronaries, while the rapid pre-systolic decompression produces a
“run-off” decrease in systolic pressure (systolic unloading) which reduces
the afterload of the left ventricle.
Michaels et al. invasively examined central aortic, intracoronary and
left ventricular hemodynamics of EECP during left heart catheterization
and found that the hemodynamic benefits of EECP are roughly compa-
rable to that of the IABP [2]. However, unlike IABP, EECP also increases
venous return, which consequently contributes to an increase in cardiac
output by the Starling mechanism without an accompanying increase in
heart rate [1,24,25]. In another invasive study by Michaels et al., the pre-
load increase by EECP was found to be counterbalanced by the afterload
reduction, thereby resulting in a neutral effect on myocardial efficiency
[26]. In the recent small Arteriogenesis Network trial, EECP was also
demonstrated to have significantly improved coronary collateral flow
index and fractional flow reserve in stable coronary artery disease pa-
tients, although the trial is limited by its small sample size [27,28,72].
In addition, EECP has also been shown to improve both regional and
global LV function in patients with coronary artery disease, as docu-
mented by one comprehensive echocardiographic study [29]. In anoth-
er study by Casey et al., changes in aortic wave reflection after EECP
were associated with decreased myocardial oxygen demand [30].
Formerly, the clinical benefit of EECP therapy was felt to be attrib-
uted to its acute hemodynamic effects, the magnitude of which was
defined as the ratio of diastolic to systolic pressure during EECP, or
the effectiveness ratio (ER). It has been shown by Suresh and his
co-investigators in a Doppler echocardiographic study that the hemo-
dynamic effects of EECP are maximized when ER is in the range of
1.5–2.0 [31]. However, Stys et al. found that ER does not predict the
immediate improvement in the angina class after EECP [7]. Michaels
AD et al. also reported that a higher ER ratio is not associated with
greater reduction in angina class compared with those with a lower
ER ratio [32]. Also, the fact that a considerable number of patients
benefit from EECP therapy in the absence of an optimal ER further con-
founds its clinical relevance. In an attempt to resolve this confusion,
Taguchi et al. investigated the hemodynamic mechanism of EECP in
relation to neurohumoral factors. They reproduced the acute hemody-
namic benefits of EECP in a group of patients with acute myocardial
infarction, and found that EECP had no effect on serum rennin, aldo-
sterone and catecholamine levels [24]. These authors also demon-
strated that EECP increased blood atrial natriuretic peptide (ANP)
concentration, but not brain natriuretic peptide (BNP). The elevation
in ANP level was concomitant with the increase in right atrial pressure
39
and pulmonary capillary wedge pressure, indicating that EECP acutely
increased atrial preload without exerting extra preload on the ventri-
cles, thereby improving cardiac performance without compromising
ventricular function. In addition, EECP does not result in early electro-
physiological remodeling of the heart, as evidenced by alterations in
the QT interval, unlike other hemodynamic-altering techniques, and
is therefore relatively safer, shown in the study by Henrikson and
colleagues [33].
Although EECP therapy is currently primarily used for chronic stable
angina pectoris in the outpatient setting, the early concept of counter-
pulsation model was developed for acute cardiac disorders such as
acute myocardial infarction and cardiogenic shock. Early studies in the
1970s that had applied EECP in the settings of acute cardiac disorders
had provided promising results [34,35]. In a recent pilot study by
Cohen et al., a portable EECP unit was applied in a small sample of pa-
tients with acute myocardial infarction with or without cardiogenic
shock in the Coronary Care Unit, who were not candidates for IABP ther-
apy. Most patients responded positively to the treatment, though the
benefit of EECP was less well documented owing to patient population
and sample size, and no adverse events were reported during or as a
consequence of EECP therapy [36]. Therefore, EECP, as a non-invasive
circulation-assisting device, appears to be a safe and feasible therapy
for patients with acute cardiac disorders. Ongoing studies with larger
sample size are warranted to further define the role of EECP in this
setting.
3. The shear stress-related effect of EECP
Results from many clinical studies have demonstrated a sustained
benefit of EECP in the treatment of patients with coronary artery
disease, from 6 months up to 5 years of follow-up, which prompted
a need for a closer scrutiny of the working mechanisms of this thera-
py beyond its immediate hemodynamic effects. Filling this gap in our
understanding, recent advances in vascular biology, highlighting the
relationship between shear stress and vascular endothelium, have
yielded insights into the disease model of atherosclerosis and how
EECP may exert a therapeutic effect.
The phenomenon that atherosclerotic plaques develop at specific
regions despite that the entire arterial tree is equally exposed to
systemic risk factors has been subjects of intense study. It has been
proposed that low endothelial shear stress (ESS) in the local hemody-
namic environment may play a critically important role in this pro-
cess. Through complex mechanoreception and mechanotransduction
pathways, low ESS ultimately leads to modulation of gene expression
40 D. Yang, G. Wu / International Journal of Cardiology 166 (2013) 38–43
resulting in endothelial acquisition of an atherogenic phenotype and
subsequent formation of an early atherosclerotic plaque. The role of
endothelial shear stress and vascular remodeling has been reviewed
in detailed by Chatzizisis and others [37]. It can be reasonably deduced
that the atheroprotective effects of EECP could also be attributed to
improving endothelial flow conditions, resulting in an increase in
ESS [2,38–40].
Vascular shear stress (τ) can be calculated according to the for-
mula [41] τ (dyn/cm2) = 4ηV / ID, where η is the viscosity expressed
in poise, V is the blood flow velocity expressed in centimeters per sec-
ond, and ID is the internal diameter expressed in centimeters. It is
recognized that physiological endothelial shear stress is within the
range of 15–70 dyn/cm 2, whereas a magnitude of 100–400 dyn/cm 2
is believed to be harmful to the endothelium. As stated previously,
intracoronary hemodynamics of EECP were characterized by substan-
tial increase in diastolic pressure and flow in the local coronaries [2].
And therefore, theoretically, without significant changes in viscosity
and vessel diameter, local ESS would see a proportional rise in response
to systemic increase in ESS. EECP-induced systemic ESS increase does
not exceed the level of 30–60 dyn/cm2, supposedly rendering benefit
without risks [40]. Whether such an increase in ESS can be directly
extrapolated to reflect an atheroprotective local ESS increase is yet
disputable. Although clinical experiences so far are in strong favor of
this hypothesis, further in vitro and in vivo hemodynamic studies are
warranted.
In this section, three of the shear-stress-related benefits of EECP
are reviewed, namely, the improvement in endothelial function and
morphology, the attenuation of oxidative stress and inflammation,
and the promotion and angiogenesis and vasculogenesis.
3.1. EECP improves endothelial function and morphology
ESS has been proven to be a major regulatory factor for endothelial
release of nitric oxide (NO) [42–44], as well as endothelin-1 (ET-1)
[45], and a physiologically appropriate level plays an indispensable
role in the maintenance of vascular homeostasis [46,47]. Therefore, it
is plausible to assume that EECP, by increasing shear stress, is able to
improve endothelial function. Validating this notion, Barsness et al.
and Masuda et al. have documented that EECP is associated with a sig-
nificant dose-related increase in plasma NO levels [1,11], as well as a
similar decrease in plasma endothelin-1 level [1] by the end of treat-
ment compared with baseline. Further, Akhtar et al. measured plasma
NO as well as ET-1 level before, during, and after the course of EECP
in patients with symptomatic coronary artery disease (CAD) and
followed them post treatment for 3 months. These authors found
that EECP progressively increases plasma NO levels and concomitantly
decreases ET-1 level over the course of therapy up to 3 months [48].
Levenson et al. found a significant increase of cyclic GMP immediately
after 1 h of EECP session both in plasma and in platelets, indicating the
acute effect of EECP on modulating vascular tone, supposedly through
the NO pathway [49]. In addition to the previous results, Tao et al.
reported that EECP partially improves endothelium-dependent vaso-
relaxation, but not endothelium-independent vasorelaxation, in an
in vivo model of arterial ring harvested from hypercholesterolemic
pigs, confirming the functional improvement of vascular endothelium
from EECP [50]. Recently, Zhang et al. observed the effect of EECP on
endothelial morphology under scanning electron microscopy and
found that EECP significantly alleviates endothelial disarray caused
by hypercholesterolemia [40].
These results vindicated the clinical findings that EECP improves en-
dothelial function in symptomatic CAD patients as measured by reactive
hyperemic-peripheral arterial tonometry index [51] and brachial artery
flow-mediated dilatation [52]. In another study by Levenson et al., EECP
was shown to improve arterial stiffness and vascular resistance in the
carotid circulation in patients with coronary artery disease [53]. In
a small sample of ischemic cardiomyopathic patients, Hashemi et al.
found that EECP improved endothelial-dependent, but not endothelial-
independent, vasorelaxation, but the benefit subsided after 1 month
[54]. Gloekler et al. further discovered that EECP promoted angiograph-
ically documented collateral growth in stable coronary disease patients,
and that this collateral promotion was correlated with an improvement
in systemic endothelial function [55]. In a recent study by Braith et al.,
EECP was shown to improve brachial and femoral flow-mediated dilata-
tion with a favorable profile of plasma markers of endothelial function
[56].
In addition to its effect on vascular endothelium, EECP is also
postulated to ameliorate the migration and proliferation of vascular
smooth muscle cell caused by low ESS. This hypothesis was verified
in the hypercholesterolemic porcine model by Zhang et al. [40]. In
this study, EECP was shown to increase shear stress in the carotid
arteries by about 2-fold, which corresponded with a significant reduc-
tion hypercholesterolemia-induced endothelial damage and arrest of
VSMC migration and proliferation, as well as collagen remodeling.
This suppression of atherosclerotic lesion, according to the authors,
is considered to be mediated by an activation of the endothelial nitric
oxide synthesase (eNOS)/NO pathway and downregulation of ERK-1/2
phosphorylation. There are, however, no clinical study to date that
addresses the application of EECP in similar situations in which VSMC
proliferation is a major clinical problem, for example, implantation of
a bare metal stent.
3.2. EECP attenuates oxidative stress and inflammation
Oxidative stress and inflammation are associated with various car-
diovascular risk factors [57,58], shown to be promoted by low endo-
thelial shear stress [37].
In Barsness et al.'s study, EECP treatment resulted in a linear dose-
dependent decrease in circulating markers associated with oxidative
stress [1]. Casey et al. studied the effect of EECP on plasma levels of
pro-inflammatory biomarkers, and found that patients in the EECP
group demonstrated a significant reduction in plasma levels of tumor
necrosis factor-alpha and monocyte chemoattractant protein-1 com-
pared with controls, indicating EECP therapy was associated with atten-
uation of the pro-inflammatory status seen in cardiovascular diseases
via its shear stress-increasing effect [59]. In pre-clinical studies, Zhang
et al. reported that the EECP-promoted endothelial shear stress increase
was found to be correlated with attenuation of atherosclerosis progres-
sion through modulation of pro-inflammatory mechanisms in terms
of suppression of MAPK-P38/NF-kappaB/VCAM-1 signaling pathway,
which was overactivated in the hypercholesterolemic porcine animals
[60].
In a recent study by Braith et al., EECP was shown to induce an
anti-inflammatory profile in patients with chronic angina on top of
improvement in angina symptoms and peripheral endothelial func-
tion. This small-sample randomized control trial found that after a
full-course of EECP, plasma levels of pro-inflammatory markers such
as tumor necrosis factor-alpha, monocyte chemoattractant protein-1,
soluble vascular cell adhesion molecule-1, high-sensitivity C-reactive
protein, and lipid peroxidation marker 8-isoprostane all decreased
significantly compared with sham control [56].
3.3. EECP promotes angiogenesis and vasculogenesis
Angiogenesis is the de novo formation of capillary vessels from
pre-existing vessels. Increased shear stress has been shown to upreg-
ulate endothelial production of growth factors such as vascular endo-
thelial growth factor (VEGF), which is involved in the complex process
of angiogenesis [61]. Therefore, it is also plausible that the shear stress
increase induced by EECP may be translated into a pro-angiogenic
effect. Primitive canine studies have shown that 1 h of EECP therapy
resulted in immediate recruitment of collateralization of the ischemic
hind limb [58]. Wu et al. has demonstrated in a canine model of acute
 D. Yang, G. Wu / International Journal of Cardiology 166 (2013) 38–43 41

myocardial infarction that chronic EECP is associated with a significant
increase in capillary density in the infarct area as well as in local
and systemic VEGF levels. These authors also demonstrated that the
increase in capillary density corresponded to improved myocardial
perfusion by 99mTc-sestamibi single-photon emission computed to-
mography [62,63].
In view of the dynamic interplay between vasodilatation and an-
giogenesis, namely the fact that vasodilatation is involved in in-vivo
angiogenesis while several angiogenic factors, such as NO, possess
vasodilatory properties [64], angiogenesis can be promoted by a robust
endothelial function and NO bioavailability, which can be achieved by
increasing endothelial shear stress. However, it must be pointed out
that collaterals in dogs develop much faster than those in men, and
therefore whether these findings in animals can be directly extrapolated
to humans is still questionable.
Vasculogenesis, on the other hand, is the spontaneous in situ
formation of new blood vessels, which requires mobilization, homing
and differentiation of endogenous endothelial progenitor cells (EPCs).
In vivo studies have identified the properties of VEGF in EPC mobiliza-
tion and differentiation [65–67]. Given the fact that plasma increases
in VEGF and other cytokines are achievable through EECP-induced
shear stress enhancement, EECP may promote EPC mobilization and
thereby promote vasculogenesis. Luo et al. have demonstrated in an
atherosclerotic porcine model that EECP increases endogenous G-
CSF, subsequently enhancing mobilization of progenitor cells and
augmenting myocardial expression of VEGF and SDF-1alpha [68]. In
the study by Barsheseht et al., a significant post-treatment increase in
CD34+/KDR+ mononuclear cells (representative of EPCs), as well as
in EPC-colony forming units were documented in EECP patients com-
pared with those treated with standard care [69]. Jewell et al. have
also demonstrated the regenerative effect of EECP in terms of gradual
increase in circulatory EPCs over 4 weeks [70]. These changes were cor-
related with improvement of symptoms and other functional parame-
ters. However, for reasons yet unknown, Kiernan et al. reported that

Table 1
Major clinical evidence of EECP relevant with proposed mechanisms discussed in the article.

Author (Ref. #) Year Subjects N Clinical improvement Other important findings

Acute hemodynamic benefits

Michaels et al. [2] 2002 CAG referral 10 N/A ● ↑diastolic and mean pressures and ↓systolic pressure
in the central aorta and the coronaries
● ↑coronary artery flow
Taguchi et al. [24] 2004 AMI 24 N/A ● ↑RAP and PCWP; ↑CI
● ↑blood ANP concentration, but not BNP
Michael et al. [26] 2009 CAG referral 10 N/A ● dose-dependent ↑RAP and aortic diastolic pressure
● ↑LV volume; ↓LV diastolic pressure
● ↑maximum positive and negative LV dP/dt
● neutral effect on myocardial mechanical efficiency
Buschmann et al. [27] 2009 Stable CAD 23 Improvement in CCS and ● ↑pressure-derived collateral flow index (CFIp)
NYHA class ● ↑fractional flow reserve (FFR)
Esmaeilzadeh et al. [29] 2009 Unrevascularizable CAD with NYHA 20 Improvement in CCS and ● ↑systolic and diastolic function parameters by
functional class III-IV NYHA class Tissue Doppler Echocardiography
Casey et al. [30] 2011 Stable CAD 42 Improvement in exercise ● ↓myocardial oxygen demand and wasted LV energy
capacity ● ↓central and peripheral arterial stiffness

Shear-stress-related benefit 1: improvement of endothelial function and morphology

Masuda et al. [11] 2001 Stable CAD 11 Improvement in treadmill ● ↑serum nitric oxide levels
performance ● ↑myocardial perfusion at rest and with challenge
Akhtar et al. [48] 2006 Stable CAD 13 N/A ● ↑plasma nitrates and nitrites
● ↓plasma ET-1
Levenson et al. [49] 2006 Patients with or at high risk of CAD 55 N/A ● ↑plasma and platelet cGMP
Bonetti et al. [51] 2003 Refractory angina 23 Improvement in CCS class ● ↑peripheral endothelial function by RH-PAT
Shechter et al. [52] 2003 Unrevascularizable refractory angina 40 Improvement in CCS class ● ↑brachial endothelial-dependent FMD but not
endothelial-independent NMD
Levenson et al. [53] 2007 CAD 30 N/A ● ↓beta stiffness index and carotid vascular resistance
Hashemi et al. [54] 2008 Ischemic cardiomyopathy 15 N/A ● ↑endothelial-dependent FMD but not
endothelial-independent NMD
Gloekler et al. [55] 2009 Stable CAD 20 ● ↑brachial FMD
● ↑coronary collateral flow index and conductance
(correlated with ↑in brachial FMD)

Shear-stress-related benefit 2: attenuation of oxidative stress and inflammation

Casey et al. [59] 2008 CAD 21 N/A ● ↓plasma levels of TNF-alpha and MCP-1
Braith et al. [56] 2010 CAD 42 Improvement in CCS class ● ↓plasma levels of TNF-alpha, MCP-1, soluble VCAM-1,
high-sensitivity CRP, and 8-isoprostane
● ↑brachial and femoral FMD

Shear-stress-related benefit 3: promotion of angiogenesis and vasculogenesis

Barsheshet et al. [69] 2008 CAD 25 Improvement in CCS class ● ↑CD34 +/KDR + mononuclear cells and colony
forming units (CFU)
● ↑FMD (correlated with ↑EPC-CFUs)
Kiernan et al. [71] 2010 CAD 13 Improvement in CCS class ● CD34+, CD133 + and CD34+, CD133 + CPC counts
and DASI scores ● DASI scores correlated with CD34+, CD133 + and
CD34+, CD133 + CPC counts
Buschmann et al. [27] 2009 Stable CAD 23 Improvement in CCS and ● ↑pressure-derived collateral flow index (CFIp)
NYHA class ● ↑fractional flow reserve (FFR)

Notes: CAG, coronary angiogram; AMI, acute myocardial infarction; RAP, right atrial pressure; PCWP, pulmonary capillary wedge pressure; CI, cardiac index; ANP, A-type natriuretic
peptide; BNP, B-type natriuretic peptide; LV, left ventricle; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; NYHA, New York Heart Association; cGMP, cyclic
GMP; RH-PAT, reactive hyperemia-peripheral arterial tonometry; FMD, flow-mediated dilatation; NMD, nitroglycerin-mediated dilatation; TNF-alpha, tumor necrosis factor-
alpha; MCP-1, monocyte chemoattractant protein; VCAM, vascular cell adhesion molecule; CRP, C-reactive protein; DASI, Duke Activity Status Index.
42 D. Yang, G. Wu / International Journal of Cardiology 166 (2013) 38–43
hematopoietic, but not endothelial, progenitor cells were significantly
mobilized in response to EECP treatment and correlated with repro-
ducible measures in clinical improvement [71]. Just recently, as men-
tioned earlier, Buschmann et al. reported the results of Arteriogenesis
Network trial, and provided the functional evidence of arteriogenesis
stimulation in terms of collateral flow index and fractional flow reserve
[27,74]. Although further studies are required before a complete under-
standing of this phenomenon occurs, these data have jointly suggested
that EECP promoted a shear stress-related effect of angiogenesis and/or
vasculogenesis.
Taken it altogether, the evidence of this shear stress-related bene-
fit of EECP is in conformity with the correlation between shear stress
and atherosclerosis elucidated in basic studies [37]. In other words,
increased endothelial shear stress seems to be a major mediator by
which the effect of EECP therapy is translated into clinical benefits
for patients with atherosclerotic diseases (Table 1).
4. Conclusion and future directions
Enhanced external counterpulsation is a safe and feasible therapy
for the management of patients with coronary artery disease, although
the exact mechanisms of action of EECP are still incompletely under-
stood. Notwithstanding other mechanisms proposed elsewhere such
as opening pre-existing collaterals, improving left ventricular function
and a peripheral training effect [73,74], the primary working principles
seem to fall under the two categories discussed above. Besides its clas-
sical acute hemodynamic benefits, current knowledge of vascular biolo-
gy renewed our perspectives in that EECP therapy increases endothelial
shear stress to a physiological favorable level, thereby producing addi-
tional therapeutic effects, in terms of regression of atherosclerosis and
promotion of neovascularization. A summary of the proposed mecha-
nisms of EECP is shown in Fig. 1.
However, EECP is currently listed only as a level IIb recommendation
in several major management guidelines for refractory angina [21–23].
The main reason for this bench-to-bedside gap is that substantial diffi-
culties exist in translating the aforementioned benefits of EECP into
robust evidence that can be repetitively documented in randomized
control trials. Such failures may be attributed primarily to poor study de-
sign, as suggested in a recent Cochrane systematic review [75], as well as
factors such as an ineffective execution of blinding (significant differ-
ences between active treatment and sham control) in clinical trials.
Albeit premature to come to a definitive conclusion based on cur-
rent data, significant ramifications remain noteworthy for future stud-
ies. First of all, the notion of a standard course of EECP therapy has
always been a total of 35 1-hour treatment sessions and never chal-
lenged, whereas, in light of the evidence, patients with atherosclerotic
diseases could presumably benefit more from prolonged sessions of
treatment. Second, for patients with prominent endothelial dysfunc-
tion (e.g. heavy smokers, diabetics, patients with Cardiac Syndrome X
[76,77] etc.) or those requiring prompt endothelial recovery (e.g. post-
PCI patients with implantation of drug-eluting stents), EECP seems to
be a reasonable treatment option adjunctive to optimal medical thera-
py, and thus its role needs to be further defined. Thirdly, since shear
stress appears to be a treatment target of more therapeutic value com-
pared to diastolic augmentation, future generations of EECP device
would be developed to aim at increasing endothelial shear stress, rather
than merely maximizing the hemodynamic effects of systolic unloading
and diastolic augmentation. And last but not the least, in view of its
efficacy, the role of EECP may be explored in the prevention and rehabil-
itation of patients with coronary artery disease.
Acknowledgment
The authors of this manuscript have certified that they comply
with the Principles of Ethical Publishing in the International Journal
of Cardiology.
References
[1] Barsness GW. Enhanced external counterpulsation in unrevascularizable patients.
Curr Interv Cardiol Rep 2001;3:37–43.
[2] Michaels AD, Accad M, Ports TA, Grossman W. Left ventricular systolic unloading
and augmentation of intracoronary pressure and Doppler flow during enhanced
external counterpulsation. Circulation 2002;106:1237–42.
[3] Lawson WE, Hui JC, Cohn PF. Long-term prognosis of patients with angina treated
with enhanced external counterpulsation: five-year follow-up study. Clin Cardiol
2000;23:254–8.
[4] Lawson WE, Hui JC, Guo T, Burger L, Cohn PF. Prior revascularization increases the
effectiveness of enhanced external counterpulsation. Clin Cardiol 1998;21:841–4.
[5] Lawson WE, Hui JC, Soroff HS, et al. Efficacy of enhanced external counterpulsa-
tion in the treatment of angina pectoris. Am J Cardiol 1992;70:859–62.
[6] Lawson WE, Hui JC, Zheng ZS, et al. Can angiographic findings predict which coro-
nary patients will benefit from enhanced external counterpulsation? Am J Cardiol
1996;77:1107–9.
[7] Stys T, Lawson WE, Hui JC, Lang G, Liuzzo J, Cohn PF. Acute hemodynamic effects
and angina improvement with enhanced external counterpulsation. Angiology
2001;52:653–8.
[8] Stys TP, Lawson WE, Hui JC, et al. Effects of enhanced external counterpulsation
on stress radionuclide coronary perfusion and exercise capacity in chronic stable
angina pectoris. Am J Cardiol 2002;89:822–4.
[9] Zheng ZS, Li TM, Kambic H, et al. Sequential external counterpulsation (SECP) in
China. Trans Am Soc Artif Intern Organs 1983;29:599–603.
[10] Lawson WE, Hui JC, Zheng ZS, et al. Improved exercise tolerance following
enhanced external counterpulsation: cardiac or peripheral effect? Cardiology
1996;87:271–5.
[11] Masuda D, Nohara R, Hirai T, et al. Enhanced external counterpulsation improved
myocardial perfusion and coronary flow reserve in patients with chronic stable
angina; evaluation by (13)N-ammonia positron emission tomography. Eur Heart J
2001;22:1451–8.
[12] Urano H, Ikeda H, Ueno T, Matsumoto T, Murohara T, Imaizumi T. Enhanced exter-
nal counterpulsation improves exercise tolerance, reduces exercise-induced myo-
cardial ischemia and improves left ventricular diastolic filling in patients with
coronary artery disease. J Am Coll Cardiol 2001;37:93–9.
[13] Fricchione GL, Jaghab K, Lawson W, et al. Psychosocial effects of enhanced exter-
nal counterpulsation in the angina patient. Psychosomatics 1995;36:494–7.
[14] Springer S, Fife A, Lawson W, et al. Psychosocial effects of enhanced external counter-
pulsation in the angina patient: a second study. Psychosomatics 2001;42:124–32.
[15] Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external coun-
terpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ische-
mia and anginal episodes. J Am Coll Cardiol 1999;33:1833–40.
[16] Arora RR, Chou TM, Jain D, et al. Effects of enhanced external counterpulsation on
Health-Related Quality of Life continue 12 months after treatment: a substudy of
the Multicenter Study of Enhanced External Counterpulsation. J Investig Med
2002;50:25–32.
[17] Barsness G, Feldman AM, Holmes Jr DR, Holubkov R, Kelsey SF, Kennard ED. The
International EECP Patient Registry (IEPR): design, methods, baseline characteris-
tics, and acute results. Clin Cardiol 2001;24:435–42.
[18] Lawson WE, Hui JC, Lang G. Treatment benefit in the enhanced external counter-
pulsation consortium. Cardiology 2000;94:31–5.
[19] Lawson WE, Hui JC, Zheng ZS, et al. Three-year sustained benefit from enhanced
external counterpulsation in chronic angina pectoris. Am J Cardiol 1995;75:840–1.
[20] Loh PH, Cleland JG, Louis AA, et al. Enhanced external counterpulsation in the
treatment of chronic refractory angina: a long-term follow-up outcome from the
International Enhanced External Counterpulsation Patient Registry. Clin Cardiol
2008;31:159–64.
[21] Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the
management of patients with chronic stable angina—summary article: a report of
the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines (Committee on the Management of Patients With Chronic
Stable Angina). Circulation 2003;107:149–58.
[22] Guideline for diagnosis and treatment of patients with chronic stable angina
(no abstract). Zhonghua Xin Xue Guan Bing Za Zhi 2007;35:195–206.
[23] Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable
angina pectoris: executive summary: the Task Force on the Management of Stable
Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341–81.
[24] Taguchi I, Ogawa K, Kanaya T, Matsuda R, Kuga H, Nakatsugawa M. Effects of en-
hanced external counterpulsation on hemodynamics and its mechanism. Circ J
2004;68:1030–4.
[25] Taguchi I, Ogawa K, Oida A, Abe S, Kaneko N, Sakio H. Comparison of hemodynamic
effects of enhanced external counterpulsation and intra-aortic balloon pumping in
patients with acute myocardial infarction. Am J Cardiol 2000;86:1139–41 A9.
[26] Michaels AD, Tacy T, Teitel D, Shapiro M, Grossman W. Invasive left ventricular en-
ergetics during enhanced external counterpulsation. Am J Ther 2009;16:239–46.
[27] Buschmann EE, Utz W, Pagonas N, et al. Improvement of fractional flow reserve and
collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial). Eur J
Clin Invest 2009;39:866–75.
[28] Pagonas N, Utz W, Schulz-Menger J, et al. Assessment of the effect of external
counterpulsation on myocardial adaptive arteriogenesis by invasive functional
measurements—design of the arteriogenesis network trial 2. Int J Cardiol;145:
432–7.
[29] Esmaeilzadeh M, Khaledifar A, Maleki M, et al. Evaluation of left ventricular sys-
tolic and diastolic regional function after enhanced external counter pulsation
therapy using strain rate imaging. Eur J Echocardiogr 2009;10:120–6.
 D. Yang, G. Wu / International Journal of Cardiology 166 (2013) 38–43
[30] Casey DP, Beck DT, Nichols WW, et al. Effects of enhanced external counterpulsa-
tion on arterial stiffness and myocardial oxygen demand in patients with chronic
angina pectoris. Am J Cardiol;107:1466–72.
[31] Suresh K, Simandl S, Lawson WE, et al. Maximizing the hemodynamic benefit of
enhanced external counterpulsation. Clin Cardiol 1998;21:649–53.
[32] Michaels AD, Kennard ED, Kelsey SE, et al. Does higher diastolic augmentation
predict clinical benefit from enhanced external counterpulsation?: data from
the International EECP Patient Registry (IEPR). Clin Cardiol 2001;24:453–8.
[33] Henrikson CA, Chandra-Strobos N. Enhanced external counterpulsation therapy:
significant clinical improvement without electrophysiologic remodeling. Ann
Noninvasive Electrocardiol 2004;9:265–9.
[34] Mueller H. Are intra-aortic balloon pumping and external counterpulsation effec-
tive in the treatment of cardiogenic shock? Cardiovasc Clin 1977;8:87–102.
[35] Soroff HS, Cloutier CT, Birtwell WC, Begley LA, Messer JV. External counterpulsation.
Management of cardiogenic shock after myocardial infarction. JAMA 1974;229:
1441–50.
[36] Cohen J, Grossman W, Michaels AD. Portable enhanced external counterpulsation
for acute coronary syndrome and cardiogenic shock: a pilot study. Clin Cardiol
2007;30:223–8.
[37] Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endo-
thelial shear stress in the natural history of coronary atherosclerosis and vascular
remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 2007;49:
2379–93.
[38] Kern MJ, Henry RH, Lembo N, et al. Effects of pulsed external augmentation of
diastolic pressure on coronary and systemic hemodynamics in patients with cor-
onary artery disease. Am Heart J 1985;110:727–35.
[39] Werner D, Michalk F, Hinz B, Werner U, Voigt JU, Daniel WG. Impact of enhanced
external counterpulsation on peripheral circulation. Angiology 2007;58:185–90.
[40] Zhang Y, He X, Chen X, et al. Enhanced external counterpulsation inhibits intimal
hyperplasia by modifying shear stress responsive gene expression in hypercho-
lesterolemic pigs. Circulation 2007;116:526–34.
[41] Gnasso A, Carallo C, Irace C, et al. Association between intima-media thickness
and wall shear stress in common carotid arteries in healthy male subjects. Circu-
lation 1996;94:3257–62.
[42] Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of
nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Na-
ture 1999;399:601–5.
[43] Corson MA, James NL, Latta SE, Nerem RM, Berk BC, Harrison DG. Phosphorylation of
endothelial nitric oxide synthase in response to fluid shear stress. Circ Res 1996;79:
984–91.
[44] Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev 1995;75:
519–60.
[45] Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein ki-
nase C and cGMP in cultured endothelial cells. Am J Physiol 1993;264:H150–6.
[46] Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells
transduce an atheroprotective force. Arterioscler Thromb Vasc Biol 1998;18:677–85.
[47] Niebauer J, Cooke JP. Cardiovascular effects of exercise: role of endothelial shear
stress. J Am Coll Cardiol 1996;28:1652–60.
[48] Akhtar M, Wu GF, Du ZM, Zheng ZS, Michaels AD. Effect of external counterpulsa-
tion on plasma nitric oxide and endothelin-1 levels. Am J Cardiol 2006;98:28–30.
[49] Levenson J, Pernollet MG, Iliou MC, Devynck MA, Simon A. Cyclic GMP release by
acute enhanced external counterpulsation. Am J Hypertens 2006;19:867–72.
[50] Tao J, Tu C, Yang Z, et al. Enhanced external counterpulsation improves
endothelium-dependent vasorelaxation in the carotid arteries of hypercholester-
olemic pigs. Int J Cardiol 2006;112:269–74.
[51] Bonetti PO, Barsness GW, Keelan PC, et al. Enhanced external counterpulsation
improves endothelial function in patients with symptomatic coronary artery dis-
ease. J Am Coll Cardiol 2003;41:1761–8.
[52] Shechter M, Matetzky S, Feinberg MS, Chouraqui P, Rotstein Z, Hod H. External
counterpulsation therapy improves endothelial function in patients with refracto-
ry angina pectoris. J Am Coll Cardiol 2003;42:2090–5.
[53] Levenson J, Simon A, Megnien JL, et al. Effects of enhanced external counterpulsa-
tion on carotid circulation in patients with coronary artery disease. Cardiology
2007;108:104–10.
[54] Hashemi M, Hoseinbalam M, Khazaei M. Long-term effect of enhanced external
counterpulsation on endothelial function in the patients with intractable angina.
Heart Lung Circ 2008;17:383–7.
43
[55] Gloekler S, Meier P, de Marchi SF, et al. Coronary collateral growth by external
counterpulsation: a randomised controlled trial. Heart 2009;96:202–7.
[56] Braith RW, Conti CR, Nichols WW, et al. Enhanced external counterpulsation im-
proves peripheral artery flow-mediated dilation in patients with chronic angina:
a randomized sham-controlled study. Circulation;122:1612–20.
[57] Aukrust P, Berge RK, Ueland T, et al. Interaction between chemokines and oxidative
stress: possible pathogenic role in acute coronary syndromes. J Am Coll Cardiol
2001;37:485–91.
[58] Cai D, Wu R, Shao Y. Experimental study of the effect of external counterpulsation
on blood circulation in the lower extremities. Clin Invest Med 2000;23:239–47.
[59] Casey DP, Conti CR, Nichols WW, Choi CY, Khuddus MA, Braith RW. Effect of en-
hanced external counterpulsation on inflammatory cytokines and adhesion mol-
ecules in patients with angina pectoris and angiographic coronary artery disease.
Am J Cardiol 2008;101:300–2.
[60] Zhang Y, He X, Liu D, et al. Enhanced external counterpulsation attenuates athero-
sclerosis progression through modulation of proinflammatory signal pathway.
Arterioscler Thromb Vasc Biol 2010;30:773–80.
[61] Gan L, Miocic M, Doroudi R, Selin-Sjogren L, Jern S. Distinct regulation of vascular
endothelial growth factor in intact human conduit vessels exposed to laminar
fluid shear stress and pressure. Biochem Biophys Res Commun 2000;272:490–6.
[62] Wu G, Du Z, Hu C, et al. Angiogenic effects of long-term enhanced external counter-
pulsation in a dog model of myocardial infarction. Am J Physiol Heart Circ Physiol
2006;290:H248–54.
[63] Wu GF, Du ZM, Hu CH, et al. Microvessel angiogenesis: a possible cardioprotective
mechanism of external counterpulsation for canine myocardial infarction. Chin
Med J (Engl) 2005;118:1182–9.
[64] Ziche M, Morbidelli L. Nitric oxide and angiogenesis. J Neurooncol 2000;50:139–48.
[65] Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascular-
ization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J
1999;18:3964–72.
[66] Kalka C, Masuda H, Takahashi T, et al. Vascular endothelial growth factor(165)
gene transfer augments circulating endothelial progenitor cells in human sub-
jects. Circ Res 2000;86:1198–202.
[67] Kalka C, Tehrani H, Laudenberg B, et al. VEGF gene transfer mobilizes endothelial
progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg
2000;70:829–34.
[68] Luo JY, Wu GF, Xiong Y, et al. Enhanced external counterpulsation promotes
growth cytokines-mediated myocardial angiogenesis in a porcine model of
hypercholesterolemia. Chin Med J (Engl) 2009;122:1188–94.
[69] Barsheshet A, Hod H, Shechter M, et al. The effects of external counter pulsation
therapy on circulating endothelial progenitor cells in patients with angina
pectoris. Cardiology 2008;110:160–6.
[70] Jewell CW, Houck PD, Watson LE, Dostal DE, Dehmer GJ. Enhanced external coun-
terpulsation is a regenerative therapy. Front Biosci (Elite Ed);2:111–21.
[71] Kiernan TJ, Boilson BA, Tesmer L, Harbuzariu A, Simari RD, Barsness GW. Effect
of enhanced external counterpulsation on circulating CD34+ progenitor cell sub-
sets. Int J Cardiol 2011;153(2):202–6.
[72] Pagonas N, Utz W, Schulz-Menger J, et al. Assessment of the effect of external
counterpulsation on myocardial adaptive arteriogenesis by invasive functional
measurements - design of the arteriogenesis network trial 2. Int J Cardiol
2010;145(3):432–7.
[73] Bonetti PO, Holmes Jr DR, Lerman A, Barsness GW. Enhanced external counterpul-
sation for ischemic heart disease: what's behind the curtain? J Am Coll Cardiol
2003;41:1918–25.
[74] Manchanda A, Soran O. Enhanced external counterpulsation and future direc-
tions: step beyond medical management for patients with angina and heart fail-
ure. J Am Coll Cardiol 2007;50:1523–31.
[75] Amin F, Al Hajeri A, Civelek B, Fedorowicz Z, Manzer BM. Enhanced external
counterpulsation for chronic angina pectoris. Cochrane Database Syst Rev 2010:
CD007219.
[76] Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective
treatment for Syndrome X. Int J Cardiol 2009;135(2):256–7.
[77] Celik T, Iyisoy A, Yuksel UC, Amasyali B. A new treatment modality in manage-
ment of patients with cardiac syndrome X: enhanced external counterpulsation.
Int J Cardiol 2008.