EECP as a Noninvasive Treatment of Endothelial Dysfunction
Cross section of an artery showing a monolayer of endothelial cells lining the inner wall of the artery. The arterial wall is composed of smooth muscle cells and collagen.
By John CK Hui, Ph.D.
Introduction
Over the past 30 years, endothelium has emerged as the key regulator in the initiation and progression of cardiovascular disease.1-4 The endothelium is the monolayer of endothelial cells lining in the direction of blood flow along the lumen of all blood vessels. The endothelial cells function as a protective barrier and facilitate bi-directional transport of macromolecules and blood gases between all tissues and circulating blood. Endothelial cells also control vasomotor function, regulating vasodilatation and vasoconstriction by the release of nitric oxide (NO) and endothelin-1 (ET-1).5,6These neurohomonal factors play a vital role in hypertension, reduction of oxidative stress and arterial stiffness. Vascular endothelium is also responsible for the regulation of angiogenic vascular remodeling, metabolic, anti-inflammatory, and anti-thrombogenic processes.
Endothelial cells also play a critical role in the process of atherosclerosis, leading to coronary, renal and peripheral artery disease. Endothelial dysfunction initiates expression of endothelial adhesion molecule-1 and monocytechemoattractant protein-1 which incorporate circulating macrophage monocytes and T-cells into the subendothelial space, changing them into macrophage foam cell, while at the same time promoting smooth muscle cell proliferation and migration, and increased platelet activity and coagulation, leading to thrombosis, atherogenesis and neointimalization.
Enhanced External Counterpulsation (EECP)
An EECP® therapy system consists of three sets of inflatable pressure cuffs wrapped around the calves, the lower and upper thighs, including the buttocks. The cuffs are rapidly and sequentially inflated, starting from the calves and proceeding upward to the buttocks during the relaxation (diastolic) phase of each heartbeat, creating a strong arterial retrograde flow towards the heart and significantly increasing blood flow to the coronary arteries at a time when resistance to coronary blood flow is at its lowest level. The inflation of the cuffs also simultaneously increases the volume of venous blood returned to the right side of the heart, providing greater filling of the ventricle for ejection. Just before the beginning of the next cardiac cycle when the heart begins to contract, all three cuffs simultaneously deflate, leaving an empty vascular space in the lower extremities to receive blood ejecting from the heart, thereby significantly reducing the workload of the heart. The inflation/deflation activity is monitored constantly and coordinated by a microprocessor that interprets electrocardiogram signals, monitors heart rhythm and rate information, and actuates the inflation and deflation in synchronization with each cardiac cycle. The inflation/deflation cycle is repeated every heartbeat, increasing energy supply to the heart, improving cardiac output, while at the same time reducing the workload of the heart. The QRS complex of the electrocardiogram is used to provide a triggering signal for the calf inflation valve to open around the peak of T-wave, the lower thigh valve will open 50 ms later, to be followed by the upper thigh valve another 50 ms later. The pressure in the cuffs will hold as long as possible to allow maximization of diastolic augmentation. Then all three-deflation valves will open at the same time around the peak of P-wave to let the emptied peripheral vasculature to receive the blood ejected by the heart, leading to systolic unloading.
There are many pathophysically pathways by which EECP® therapy achieves its long-term clinical beneficial effects.7 There is evidence of improved endothelial function via the hemodynamic effects of increased shear stress on the arterial wall, reducing arterial stiffness and providing protective effects against inflammation, thereby inhibiting intimal hyperplasia and atherosclerosis. There is also evidence suggesting that EECP therapy triggers a neurohomonal response by improvement of endothelial function that induces the production of growth and vasodilatation factors, which together with the hemodynamic effects of increasing pressure gradient across the occlusive site during EECP® therapy, promotes the recruitment of new arteries, while exisiting blood vessels dilate and normalize in function. The recruitment of new arteries, known as “collateral blood vessels”, bypasses blocked or narrowed vessels and increase blood flow to ischemic areas of the organs that are receiving an inadequate supply of blood. A summary of the proposed mechanisms of action of EECP therapy is shown in the following diagram:
EECP® Therapy: Mechanisms of Action
Acute Hemodynamic Effects
?Increase shear Stress Systolic Unloading
?Diastolic Augmentation ?Increase Cardiac Output
Improve Endothelial Function
?Vasodilation: NO↑ ET-1↓ Vascular resistance ↓
?Arterial Stiffness ↓
?Intimal Hyperplasia ↓
?Circulating Endothelial Progenitor Cell ↑
?Angiogenesis: microvascular density↑
?Proinflammatory Cytokines and Adhesion Molecules: TNF-α↓, MCAP– 1 ↓
Reduce hypertension
Improve Blood Flow
Reduce atherosclerosis
Clinical Benefits: Sequential inflation of three sets of cuffs at the end of systole Lower ThighCuffsUpper Thigh CuffsCalfSimultaneous deflation of all three sets of cuffs at the end of diastole Lower ThighUpperThighCuffsCalf
Published clinical data showing effectiveness of EECP therapy in improving endothelial dysfunction
Historically, an external counterpulsation (ECP) device is a cardiac assist device that reduces the workload of the heart and increases energy supply to the myocardium. The objectives of ECP devices are the maximal reduction of systolic blood pressure so that the heart does not have to generate high pressure to eject the volume of arterial blood for the metabolic need of the body, and maximal augmentation of diastolic pressure to increase coronary perfusion pressure to increase coronary blood flow when resistance to coronary flow is at its lowest level. The optimal ECP operation is to achieve the maximization of the ratio of the area under the diastolic pressure to the area under the systolic pressure.
1. Acute hemodynamic effects of EECP (Enhanced External Counterpulsation): Increase cardiac output and coronary blood flow
The physiological and clinical goal of EECP is the improvement of cardiac function and increase of cardiac output, as demonstrated by the increase of velocity of blood flow in the descending aorta using Doppler echocardiography.8,9Systolic time velocity integral as a measure of stroke volume (SV) increased up to 60-70% over control with the heart rate (HR) remaining stable, demonstrating a significant increase in cardiac output. EECP also created a significant diastolic retrograde blood flow, generating a bi-directional pulsatile fin the descending aorta, increashear stress on the endothelium.
EECP also resulted in a dramatic increase in intracoronary pressure and intracoronary flow velocity measured by using a coronary catheter sensor-tipped guidewire.10 Coronary diastolic pressure increased 93% from 71 10 at baseline to 137 ± 21 mm Hg durinEECP, p<0.0001; with a decrease icoronary systolic pressure of 15%from 116 ± 22 to 99 ± 26 mm Hg, p=0.002. The intracoronary average peak velocity increased 109% from 11 ± 5 at baseline to 23 ± 5 cm/sec during EECP, p=0.001. The signific
inDescending Aorta ControlDuring EECP Stroke volume Diastolic retrograde flow Doppler echocardiography of the descending aorta
2. Effects of EECP pulsatile blood flow: increase endothelial shear stress Endothelial shear stress
flowing blood on the endothelial surface of the arterial wall and is expressed in un 2222
tress is proportional to the product of the blood viscosity (μ) and the spatial gradient of blood velocity at the wall. Low endothelial shear stress modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque.11 Therefore the significant increase of pulsatile, oscillatory flow in the aorta durEECP treatment provides a form of “massage” on the endothelium and improves its function. Effect of EECP on endothelial shear stress has been reported in an animal moZhang in 112
ultrasound system during EECP in thebrachial artery was significantlcompared with the pre-EECP measurement (24.62±4.74 versus 59.48±13.60 cm/sec, p<0.001). Theinternal diameter (id) of the right brachial artery was not significantly changes durinEECP (1.65±0.42 versus 1.68±p<0.05). The blood viscosity (μ) wa3.8±0.4 mPa (0.038±0.004 poise).Thpeak diastolic endothelial shear stress (τ) d τ (dynes/cm2) = (4 μ V) / (id) Peak diastolic endothelial shear stress during EECP increased more then 2-
3. Blood vessels vasodilate in response to an increase of flow through rather to the endothelial shear stress. Conversely, low shear stress leads to constremodelvasodilation occurs in the earliest stages of atherosclerosis, and this endothelial dysfunction is now considered to be the link between such risk factors as dyslipidemia, hypertension, diabetes mellitus, cigarette smoking, hyperhomocysteinemia, and aging to cardiovascular disease.13,14 The endothelial response to shear stress activates a varietysignalingpathways, including endotheoxidesynthase (eNOs), an enzyme rethe synthesis of nitric oxide (NO), the key endothelium-derived relaxing factor that plays a† p< 0.05 versus CHOL group 150200eNOs (% of control) †eNOsring EECP was calculated using the formula: 10.71 dynes/cm2; p<0.001).tone and reactivity. EECP has been shown to increase the expression of eNOs by Zhang and co-workers in a hypercholesterolemic pigs model using Western blotting technique.12 Expression of eNOs was significantly decreased in the group of pigs (N=28) fed with high-cholesterol diet for 15 weeks compared with the 7 pigs with normal diet served as control (p=0.009). 1 hour daily of EECP for 34±2 hours was initiated in 17 pigs after 8 weeks of atherogenic diet and eNOs expression of the EECP treated group was 3.16 times that of thecholesterol group (p=0.023).
4. EECP therapy increases the release of nitric oxide and reduces. In response to endothelial shear stress, Nitric Oxide (NO) is synthesized in thIn addition, NO also inhibits platelet and white cell activation and maintains the vascular smooth muscle cells in a nonproliferative state. More importantly, NO interacts with products of oxidative stress such as superoxide and hydrogen peroxide. Oxidative stressproduced from any cardiovascular risk factors is one of the leading causes of endothdysfunction. EECP
published later in 2006.16 This study examined whether the flow mediated increase in endothelial shear stress would activate plasma levels of the potent vasoactive agents ET-1 and NO. Thirteen coronary disease patreceived 1-hour daily EECPtreatment for a total of 36 hourand their ET-1 and NO were measured serially at baseline (Control), after the 1st, 12th, 24and 36th hours of EECP, and at 1 and 3 months post-EECP. During the course of treatment, plasma NO progressively increased and plasma ET-1 progressively decreased. After 36 hours of EECP, there was a 62 ± 17% increase in plasma NO compared with baseline (43.6 ± 4.27.1 ± 2.6 μmol/L; p<0.0001),a 36 ± 8% decrease in plasm1 level (76.7 ± 9.5 versus 119.8.5 pg/L; p<0.0001). At 3 months after completion of EECP, NO remained 13 ± 11% above baseline (p=0.002), and ET-1 remained 11 ± 10% below baseline (p=0.0068). These results demonstrate that EECP therapy has a dose related, sustained effect in stimulating endothelial cell production of the vasodilator, NO, and in deceasing production of the vasocontrictor, ET-1, supporting the hypothesis that EECP improves endothelial function. In another study, Masuda
and colleagues
demonstrated that EECP significant increased plasma NO levels compared with baseline in 1patients with chronic stable anginthe day after the start of EECP, and 1 week, 1 month after completion of35 hours of daily 1-hour EECP treatment (p<0.02).17 The treadmill exercise time, time to 1 mm ST-segment depression, perfusion in ischemic regions of the myocardat rest and during dipyridamole stress measured by 11N-ammonia positron emission tomography inthese patients also improved signifendothelial function via increase oto the observed clinical benefits of EECP treatment.
There are s
withendothe
follow-up compared with patients with preserved endothelial function.18,19 More importantlythe observation that an intervention improves endothelial function in a group of patients suffering from cardiovascular disease suggests that the intervention will also reduce cardiovascular risk.20 Currently the most promising noninvasive endothelial function testinthe endothelial-dependent, flow-mediated dilation of the brachial artery using high-resultrasound. In 2003
that improvement in per
EECP treatment in patients with symptomatic coronary artery disease (CAD).21 Reactive hyperemia-peripheral arterial tonometry (RH-PAT), a noninvasive method to assess peripheral endothelial function by using a device manufactured by Itamar Medical in measuring reactive hyperemic response in the finger (Endo PAT 2000, FDA 510k032was performed in 23 patients with refractory angina undergoing a 1-hour daily EECP total course of 35-hour treatment. In each patient RH-PAT measurements were performed before and after the first, at midcourse (17thhour), and after the last EECP course. In addition, RH-PAT response was assessed one month after completion of EECP therapy. RH-PAT index, a measured of reactive hyperemia, was calculated as the ratio of the dpulse volume during reactive hyperemia divided by that at rest. EECP was associated withsignificant immediate increase in average RH-PAT index after each treatment period (p<0.05). In addition, average RH-PAT index at one-month follow-up was significantly higher than that before EECP therapy (p<0.05), demonstrating EECP therapy provided long Nitric Oxide measured by the Griess method in 11 CAD patients. Control: before EECP therapy. Next day: 1 day following completion of 35-hour course of therapy. 1 week: 1 week after completion of therapy , and 1 month: 1 month after completion. # p<0.02 vs control, and p<0.01 vs next day.
improvement of endothedysfunction in patieCAD. No major adverse cardiovascular evennoted during the study perio In addition to RH-measurement of endothelial function, Canadian
Cardiovascular
function (CCS) class and Duke Activity Status Index (DASI) score were uassess the clinical benefEECP therapy. EECP therled to an improvement by oCCS class in 12 (52%) patients and by two CCS class in 5 (22%) patients, whereas 6 (26%) patients showed no change in CCclass.
in this study, 74% experience an improvement in their functional status. Similarly, 17 (74%) patients reported improvement in their functional status, as measured by the DASI score. Moreover, average RH-PAT before initiation of EECP therapy and one month after completion of therapy significantly increased only in patients showing improvement functional CCS class or DASI score. Patients failed to show improvement in their endotheliafunction also failed to improve their cardiac function class and status, demonstrating a direct relationship between endothelial dysfunction and cardiovascular disease, supporting the role of EECP as an effective therapeutic strategy for patients with endothelial dysfunction. 1.0 0.5 01st h17th h35th h1-month follow-up *N=18Pre-Post-*p<0.05; †p<0.05 vs pre EECP index on 1st, 17th and 35th hr J Am Col Cardiol2003:41101761-8*PAT Index 2.0Despite significant cardiac risk profiles and advanced CAD among patients included
Results of the Mayo Clinic were supported by another paper in 2003 by Shechter and co-workers using the endothelial-dependent, flow-mediated dilation (FMD) of the brachial artery with high-resolution ultrasound technique to assess endothelial vasomotor function.22 This is a prospective age-matched controlled study. The endothelial function in 20 consecutive CAD patients (15 males), mean age 68 ± 11 years, with refractory angina pectoris CCS class III and IV, unsuitable for coronary revascularization was assessed by FMD before and after their ECP treatment. These measurements were compared with 20 matched control CAD patients (17 males). There were no significant group differences in baseline characteristics between the ECP and Control group, with 75% in CCS class IV. There were no significant changes in concomitant medication use and no serious adverse effects throughout the study. After completion of 35 hours of daily 1 hour ECP treatment, FMD improved significantly from baseline 3.1 ± 2.2% to 8.2 ± 2.1%; p=0.01), whereas there were no changes in the Control group within the 2-month period. ECP also improved angina symptoms by a reduction in mean number of sublingual nitrate tablets consumption per day (from 4.2 ± 2.7 to 0.4 ± 0.5; p<0.001), compared with no change in the Control group (4.5 ±2.3 to 4.4 ± 2.6; p=0.87). The mean CCS class also improved significantly in the ECP group (3.5 ± 0.5 to 1.9 ± 0.3; p<0.0001), with no change in the Control group (3.3 ± 0.6 to 3.5 ± 0.5; p=0.89). This study demonstrates that ECP intervention compared with controls results in significant improvement in endothelial dysfunction and cardiac function status.
In 2004, Bonetti and co-workers reported a very interesting case of a 29 year-old woman with chest pain despite medications with various calcium antagonists, β-blocker and antidepressant.23 Coronary angiography revealed structurally normal vessels. Administration of adenosine into the left coronary system showed an intact endothelium-independent microvasculature response; with a normal coronary flow reserve of 2.5. However, intracoronary infusion of grades doses of endothelium-dependent vasodilator acetylcholine (10-6 to 10-4 mol/L) into the left anterior descending (LAD) artery was associated with a progressive decrease in coronary flow, ultimately resulted in complete LAD occlusion, compatible with the presence of severe endothelial dysfunction of both the coronary microvasculature and the coronary macrovasculature. Despite the addition of an angiotensin-converting enzyme (ACE) inhibitor and L-arginine supplementation to the patient’s existing treatment regimen, the patient symptoms worsened during the subsequent months and severely impaired her functional capacity. Patient status changed from CCS Class III to CCS class IV. Patient was treated with 35-hour of daily 1-hour course of EECP. After completion of EECP, the patient was free of angina and was able to perform her daily activities without the dyspnea or fatigability experienced before EECP. At the last follow-up visit 3 months after completion of EECP therapy, the patient was symptom free with a medication regimen of calcium channel blockade, ACE inhibitor and L-arginine supplementation. Endothelial dysfunction is considered to be major key early event in atherosclerosis. This case is interesting because the patient had no traditional cardiovascular risk factors and no manifestations of advanced atherosclerotic disease and Baseline 2-month after EnrollmentJ Am CollCardiol 2003;42:2090-5
yet suffered from severe coronary endothelial dysfunction. The sustained clinical improvement after a standard course of EECP in a patient with severely symptomatic coronary endothelial dysfunction supports the concept that EECP can be used as a treatment of endothelial dysfunction.
6. Effects of EECP treatment on arterial stiffness, a manifestation of endothelial dysfunction
Arterial stiffness is a strong independent predictor of cardiovascular outcomes above and beyond traditional cardiovascular risk factors in both healthy subjects and patients with high risk of coronary artery disease.24,25Muscular arterial stiffness is related to smooth muscle tone and NO bioavailability. Under basal conditions, NO is continually released from healthy endothelial cells and serves to inhibit adhesion of platelets and leukocytes to the vessel wall. After diffusion to the media, NO activates the enzyme guanylcyclase, which increases formation of cyclic guanosinemonophosphate (cGMP) to relax smooth muscle cells and maintain vascular patency and distensibility. When the endothelium becomes dysfunctional, bioavailability of NO is limited, impairing smooth muscle cell relaxation, leading to arterial stiffness.