SECTION TWO:  CLINICAL STUDIES - HEART ATTACK

SECTION THREE:  PHYSIOLOGIC STUDIES

 

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SECTION ONE:  CLINICAL STUDIES - ANGINA

1.  Enhanced External Counterpulsation as an Adjunct to Revascularization in Unstable Angina. Lawson WE, Hui JCK, Oster ZH, et al. Clinical Cardiology 1997; 178-180. 

This case report illustrates the capacity of EECP to revascularize the heart and control symptoms in patients who have not benefited from balloon angioplasty or bypass surgery. The authors describe a 58 year old man who required two separate bypass surgeries, six rounds of angioplasty involving over 20 narrowings, and multiple heart catheterizations, all within a 26 month time period. Finally, one artery closed off completely and further angioplasty was not possible. The patient was then begun on EECP and experienced a "dramatic" reduction in symptoms within 3 weeks. Upon completion of a 120 hour course, this patient’s stress nuclear scan normalized and angina fully resolved. Three years out from EECP he remains asymptomatic.

Well, if you come to my office Monday through Friday for seven weeks you ought to get better. But will the improvement hold? Will angina remain in check, or will the augmented collaterals close down, just as an artery might renarrow following an initially successful angioplasty? Will EECP provide more than transient relief ?

To answer these questions, Lawson’s group followed the course of their initial 18 patients over a three year period, and reported their findings in this ’95 article. Medication changes were permitted, and 8 patient received booster courses of EECP, but aggressive risk factor reduction maneuvers were not carried out. What happened to these patients?

Of the 4 patients with improved angina but unimproved nuclear scans, one required bypass and another a balloon angioplasty, but the other two patients remained free of disabling angina. Of the 14 whose scans improved, two sustained events - one a heart attack and one  patient underwent bypass; one patient was lost to follow-up but the other 11 remained free of significant symptoms. 10 underwent a repeat stress nuclear scan; in 8 the scan remained improved.                 

For the group as a whole there was a 23% event rate (one heart attack and three revascularizations), no deaths, and in 60% the nuclear scan remained normal and angina remained minimal.  76% of these patients in whom standard therapy had failed remained free of disabling symptoms and event free 3 years after undergoing EECP.

Of the "responders", the 14 patients whose thallium scans improved following EECP, the three year event rate was 15%, and the thallium scan remained improved in 80% of those who remained event free.

Three year follow-up is fine, but what’s going to happen at five years? In this report Lawson and associates summarize the five year outcome of 33 patients treated with EECP between 1989 and 1992 at the State University of New York.  Keep in mind that this was a sick group of patients; 43% had multivessel disease, 45% had sustained a heart attack, 61% had undergone bypass or angioplasty, and 8 had required both.  None were felt to be good candidates for further revascularization.  

Over the five year follow-up period, medication changes were permitted, and 13 of the 33 patients underwent booster session of EECP.  For the entire group, five year survival  following EECP was 88%. 31% of the patients required a  hospitalization; 14% sustained a heart attack and 21% underwent a revascularization procedure. 69% of  the patients stayed out of the hospital. Overall, 60% of the original 33 patients undergoing EECP for refractory angina were alive and well, event free, and remained out of the hospital during the five year follow-up period.            

So far we have talked about thallium scans, event rates, and mortality, the "hard data" that we cardiologists like to read about in our journals. This information is important to us, but as a patients you will be more concerned with the effect a treatment has on your quality of life. In this study, Fricchione and associates looked at the effect of EECP on a "hard" endpoint, the cardiac nuclear scan, and several "human" endpoints, such as the patient's stress level and quality of life.  Let’s see what they found.

The nuclear scans normalized in 75% of the patients, not a surprise to you at this point. The researchers also showed that patients did not experience significant stress in association with their EECP treatments. Following EECP, average angina frequency fell from 3.9 to 0.6 episodes per three months.  NTG requirement decreased from 2.3 to 0.1 tablets over the same time period. Chest pain severity on a four point scale fell from 2.9 to 1.7. Each patient was questioned as to the effect EECP had on their quality of life and the group responses are listed below:

Research tells us that intimacy with one’s spouse, interaction with family members, and involvement with others in our work, community, and church activities has a positive effect on our health and sense of well being.  EECP seems to help here, improving our quality of life, not just the "hard end points".

10.  Enhanced External Counterpulsation Protects Coronary Artery Disease Patients from Future Cardiac Events. S. Karim et al 1^st International Congress on Heart Disease - New Trends in Research, Diagnosis, and Treatment. The Journal of Heart Disease 1:1 May ’99

External Counterpulsation - Review Article.  Xu-Yu-yun, Hu Da-yi, & Zheng Zhen-sheng. Chinese Medical Journal 103(9): 762-71,1990

 

The published studies of EECP give us a clear message: EECP is an effective treatment for angina.  In each study, be it American, Chinese, or Indonesian, just over 90% of patients improve. That EECP works well short term is now clearly established, but can EECP, or a program of EECP, have an effect on long term outcome? Dr. Lawson’s paper, which we reviewed as article 4, showed us that five year outcome following EECP, when used to treat refractory symptoms in inoperable patients, was similar to that of low risk patients who underwent elective bypass surgery. But Lawson’s study involved only 33 patients. What effect will EECP have when larger groups of patients are studied, and for longer periods of time? Can a program based on EECP make a long term difference?

Karim and associates treated 117 patients with EECP between 1/92 and 12/97. Their outcome through 12/98 was then compared with that of 198 coronary patients who were treated over the same time period with standard drug therapy. The number of cardiac events (cardiac death, heart attack, need for invasive revascularization) occurring in each group over the seven year follow-up period was recorded. The average number of days elapsing between the initiation of therapy and the development of an event was calculated. Here’s what Karim found:

 

	Drug Group	EECP Group
Mean # Event Free Days	958	1,010
Cardiac Death	9.6%	4.3%
Heart Attack	4.5%	1.7%
Revascularization	.5%	1.7%

 

Karim found that patients treated with drug therapy alone were 2.3 times more likely to experience an adverse event during the seven year follow-up period. Unlike the MUST-EECP study (Article 8), Karim’s study was not randomized or double-blind. The EECP patients knew they had received EECP. The drug group knew that they hadn’t. Still, the results are impressive, and I like the idea of my patients being 2.3 times less likely to experience an adverse cardiac event.

In China, medical records are centralized, and standard measures are used to asses symptom severity and a patient’s response to treatment. By 1990, 1,800 EECP centers were up and running in China. In this 1990 paper, Dr. Xu Yu-yun and colleagues describe the short term effects of EECP in just over 6,000 patients. Long term outcome of 102 patients treated with EECP is compared with that of a similar group of coronary patients who received standard drug therapy alone. Here’s what they found:

 

Short-term effects on symptoms and EKG appearance were assessed in 6,116 patients treated with EECP

Short-term	Symptoms	EKG
Significant Improvement	52.6%	20.5%
Improvement	30.3%	47.8%
No Change	8.0%	30.5%
Deterioration	0.2%	1.2%
Total Effective Rate	92%	68.3%

    Here again, just over 90% of patients treated with EECP improved.

 

Long-term results were measured in 102 EECP patients; 23, 39, & 53 were followed for 7, 6, & 5 years post EECP respectively. 19, 32, & 52 patients treated solely with medication were followed over the same time periods.

 

Total Effective Rate - Symptoms

Long-term:  Symptoms	EECP Group	Drug Group
5 year follow-up	55.8%	33.3%
6 year follow-up	67.9%	48.1%
7 year follow-up	73.9%	21.3%

 

Total Effective Rate - EKG

Long-term:  EKG	EECP Group	Drug Group
5 year follow-up	63.6%	31.2%
6 year follow-up	67.9%	20%
7 year follow-up	61.5%	46.8%

 

Cardiac Death Rate

Cardiac Death	EECP Group	Drug Group
First Year	4.9%	13.5%
By Eighth Year	7.7%	30.3%
Overall	8.8%	30.3%

 

I think I’d want to be in the EECP group. Again, this was not a randomized, double blind study, but it involved a large number of patients and points to a definite, beneficial effect of EECP on long term outcome. In interpreting these numbers, keep in mind that in China EECP is often not just a one time treatment; Chinese patients not infrequently receive booster and maintenance sessions. In China the goal is to keep people healthy and out of the hospital, at the lowest possible cost, so they’re not shy about the use of EECP. They know that EECP helps long term. The question for us is, just why does EECP help long term? Could EECP have a favorable effect on atherosclerosis? Could EECP be altering our biochemistry in a positive way? Articles 6 through10 in the physiology section discuss the favorable effect of EECP on several of the angiochemicals that regulate cardiovascular health. 

 

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11.  Treatment Benefit in the Enhanced External Counterpulsation Consortium.  Lawson, W, et al Cardiology 2000;94:31-35

The American outcome studies have all been positive, but these studies were carried out at medical school affiliated cardiology programs, involving selected cohorts of patients, in the controlled, university hospital setting.  Some treatments, especially new treatments, certainly seem to work well when carried out by super specialists at academic centers, but then not so well, when carried out by general cardiologists, on the patients we see in the community setting.  Could EECP be such a phenomenon – only of academic benefit?  Is it going to work on a large scale, outside of the university hospital setting

The International EECP Registry was founded to help answer these questions; through 3/00, 3,788 EECP patients have been entered.  In this report from the registry, involving 2,991 patients treated between 1/97 and 3/00 at 84 American EECP centers, outcome data from 2,289 with complete follow-up is analyzed.  EECP providers ranged from solo practitioners to large multispecialty groups to university hospitals.  All patients had angina upon entry, with an average Canadian Functional Class of 2.8.  What happened with EECP performed in the community setting?

First of all, the treatment was well tolerated and patients rarely deteriorated.  0.2% of the 2,289 patients deteriorated by 1 functional class.  Of the 91 adverse events experienced amongst these 2,991 individuals during their course of EECP, the vast majority were musculoskeletal, cutaneous, or non-cardiovascular and totally unrelated to their EECP treatments- see chart below.

Adverse events among 2,991 EECP patients
Category of Events	Number	Percentage
Total	91	3 %
Musculoskeletal & Skin	23	0.8 %
Non CV & Unrelated to EECP	52	1.7 %
Myocardial Infarction	8	0.3 %
Angina or Silent Ischemia	5	0.2 %
Arrhythmia	2	0.07 %
Pulmonary Edema	1	0.03 %

 

While only 0.2% of patients deteriorated during EECP, of those in classes II-IV pre-EECP, 73.4% improved by at least one level while 26.5% remained in their pre-treatment class.  Overall, mean functional class improved from 2.78 to 1.81.

As you would expect, the relative gain from EECP was proportionate to the severity of symptoms pre-treatment.  Amongst patients with class III-IV symptoms pre-treatment, mean functional class improved from 2.99 to 1.84.  Anginal class improved by 2 or more levels in 49% of those in class IV pre-EECP, and in 34.9% of those in class III.  Women did just as well as men, and patients treated in their physician’s office did just as well as those treated at a university hospital EECP program.  

 

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12.  The Safety and Efficacy of Enhanced External Counterpulsation as Therapy for Unstable Angina.  Arora, A, et al  Circulation 102:18 Supplement II Oct. '00 Abstract 2982

We have a few studies demonstrating the benefit of EECP in heart attack (acute MI), while the majority of American papers deal with the effects of EECP in persistent but stable angina.  Will EECP be effective in unstable angina, chest pain that is of new onset, or suddenly worse than that previously experienced by the patient?  EECP takes weeks to have an effect, so we really can’t treat unstable angina with EECP in the office setting, but EECP is available at many American hospitals, so looking at its effect in unstable angina is reasonable.  Of the first 832 patients included in the International EECP Registry, 21 carried the diagnosis of unstable angina.  Prior CABG was more prevalent in the unstable group, ejection fraction was lower (36 vs. 46%), and multivessel disease was more frequent (95 vs. 77%), while risk factors and many other clinical parameters were similar.

83% of the stable angina patients completed an average 34.3 hours of treatment, while 73% of the unstable patients completed an average 30.9 hours.  The degree of diastolic augmentation was higher in the stable patients.  Adverse events during treatment were not statistically different between the groups.  Both groups showed substantial reduction in angina, with 74% of the stable patients improving by at least one functional class, and 80% of the unstable patients improving to the same degree. NTG requirement and quality of life parameters improved to a similar degree.

EECP may thus be of value in dealing with the patient with unstable angina.  The papers by Taguchi (Heart Attack section – article 4) and Fujita (Physiology section – article 15) tell us that heparin anticoagulation is not a contraindication to EECP, and we know from clinical experience that EECP does not interfere with the action of anti-anginal medications.  Formal clinical studies of EECP in unstable angina are on the drawing board.  In the future, we may be using EECP to “cool down” the unstable angina patient, or to “tune-up” their status in preparation for angiography or revascularization.  

 

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13.  Enhanced External Counterpulsation in the Treatment and  Rehabilitation of  Coronary Patients in Indonesia.  Karim et al.  Asian Cardiovascular & Thoracic Annals 1995, Vol. 3, No. 1

External counterpulsation started out as an American idea. 25 years of Chinese clinical research and improvements in engineering have given us the Enhanced External Counter Pulsation device that we use today. EECP is the standard of care in China; somewhere between 500,000 and a million patients have been treated. While the "return" of external counterpulsation is new to the US, EECP is already an international treatment. Karim’s article tells us that EECP works just as well in Indonesia as it does in the US. Using the same protocol as in the American studies, Karim’s group demonstrated a 26% increase in treadmill exercise time following EECP. Nuclear stress scans improved in 87% of their patients, fully normalizing in 24%. Angina and functional class improved in all.

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14.  Effects of Enhanced External Counterpulsation on Stress Radionuclide Coronary Perfusion and Exercise Capacity in Chronic Stable Angina Pectoris.  Stys, P, et al.  Am. J. Cardiology 2002;89:822-24.

Dr. Lawson (article 7 - this section) showed us, in angina patients with 1 or 2 vessel disease, that same distance nuclear perfusion scans improve in 95 and 90% of patients respectively.  In his group's initial report on the effects of EECP on 18 patients with refractory angina (article 2), average treadmill time increased by 96 seconds for the entire group, and by 114 seconds in patients whose nuclear scans improved.  In the MUST-EECP study, treadmill times improved by 44 seconds and time to ST depression (the EKG signal that coronary blood flow is strained) by 42 seconds.  These are benchmarks against which we in the medical community can compare our own work (We do not routinely carry out pre- and post-EECP stress tests on all of our patients.  Nearly all of our patients had a pre-EECP stress test, and we repeat the study post-EECP only when we have a patient care related question that needs to be answered.  Some patients can't exercise due to orthopedic limitations, while others were doing so well that we don't need to re-stress them.  61 of our first 181 patients underwent serial pre- and post-EECP stress studies.  Of these 61 patients, treadmill time increased in 90%, on average by 94 seconds, a 22% increase from baseline - please see Patient Outcomes section for more information).  

In this study, Stys and his associates looked at the effect of EECP on functional class, treadmill time, and nuclear scan findings in 175 angina patients undergoing EECP at 7 centers in the US, Europe, and Asia.  At 4 centers, pre- and post-EECP nuclear scans were carried out at the same treadmill exercise level (apples to apples comparison), while in 3 centers the scans were recorded at the maximally tolerated exercise level.

At the 4 centers where same distance nuclear scans were carried out, the scans improved in 81 of 97 patients, 83%, and in the other 16 patients there was no change.  The scan did not worsen in any.  At the 3 centers comparing the scans at the maximal tolerated exercise level, treadmill time was found to increase on average by 48 seconds (397 pre- to 445 seconds post-EECP).  In these patients, where we are looking at the adequacy of coronary blood flow at a heightened demand (no longer an apples to apples comparison), the scans improved in 42 of 78 patients, or 54%.  In 4% the scans worsened while in 42% no significant change was noted.  Clinically the patients did well.  85% improved by at least 1 functional class and 15% improved by 2 (see graphic).  This study fits with what we already know.  We know that nearly every patient improves clinically with EECP.  EECP doesn't open up blocked arteries, so we're not distressed with only a 54% scan improvement at a greater exercise level.  We expect EECP to improve endothelial tone, increase Nitric Oxide elaboration, and improve collateral flow, so we expect the 83% improvement in the same-distance scans.  A same-distance improved scan is something that we like to see, as article 4 showed us that an improved same distance perfusion scan correlated with a good 5-year post-EECP outcome.

 

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15.  The Improvements in Exercise Tolerance Post Enhanced External Counterpulsation in patients with Chronic Refractory Angina are related to Diastolic Augmentation.  Brown, A, et al.  Heart 2001;85(Suppl I): page 41, Abstract 125.

When our kids were younger, my family participated in Project Children; every summer we would host a child from Northern Ireland in our home.  Some of the kids had health problems, so we needed to make contact with their physicians at home.  We made a lot of friends and contacts, and while our kids are now in high school and college, we have maintained our Irish connections.  One thing led to another; my wife has continued her education through Trinity College in Dublin, achieving her Masters degree in Law, and my daughter is an undergraduate at the same institution, so I was delighted to see that EECP is now available in Ireland (another reason to visit my daughter).

In the communication abstracted below, Brown and colleagues report treatment outcome in 40 inoperable, refractory angina patients who received 35 hours of EECP.  Treadmill time, functional class, and quality of life parameters were recorded pre- and post-EECP.  Dr. Brown also looked at the level of diastolic augmentation achieved (reflecting the technical ability of EECP to increase aortic and coronary artery diastolic pressure) at the first session.   

	Pre-EECP	Post-EECP
Exercise Time	6:18	8:11
Class 3-4 Status	54%	13%
Class 1-2 Status	46%	87%
Peak Augmentation	.96	1.65
Hospital Days per Year	14.5	7.8

Treadmill time increased by just under two minutes, and post-EECP, nearly all of the patients were in Functional Class 1or 2, just as we have seen in the Chinese, Indonesian, and American studies.  Peak augmentation reflects the elasticity of our great vessels, and it is interesting to see that this parameter improves with EECP treatment.  Utilizing the SF-36 Quality of Life and the Seattle Angina Questionnaires, significant post-EECP improvements  were noted in physical functioning, general health, energy, emotional health, and social functioning.  EECP certainly cut down their need for in-hospital care, with a nearly 50% reduction in hospital days per year, pre-EECP vs. post-EECP.  This saves the Irish health care system a lot of pence and pounds, but it may or not be a good thing for the patients involved, because if you are hospitalized in Ireland, every day at 3 PM a nurse with green eyes and red hair comes by and gives you a large glass of Guinness.  On the other hand, most inoperable and previously refractory angina patients would prefer to enjoy their Guinness at home, and not in the hospital.

 

SECTION TWO:  CLINICAL STUDIES - HEART ATTACK

1.  Clinical Assessment of External Pressure Circulatory Assistance in Acute Myocardial Infarction. Amsterdam EA, et al. American Journal of Cardiology 1980; 45: 349-56

2.  Management of Cardiogenic Shock. Soroff HS, et al. Journal of the American Medical Association; 229:1441-50

3.  New Sequential External Counterpulsation for the Treatment of Acute Myocardial Infarction.  Zheng-sheng Zheng et al  Thoracic Artificial Organs 8(4): 470-77, Raven Press, New York 1984 International Society of Artificial Organs

4.  Comparison of Hemodynamic Effects of Enhanced External Counterpulsation and Intra-Aortic Balloon Pumping in Patients With Acute Myocardial Infarction.  Taguchi, I, et al The American Journal of Cardiology 2000;86:1139-41  

5. External Counterpulsation increases capillary density during experimental myocardial infarction.  Huang, W, et al  Journal of the European Society of Cardiology 1999;20(Abstract Supplement):168

6. Effect of enhanced external counterpulsation on circulating and tissue Angiotensin II in experimental myocardial infarction.  Lu, L, et al Journal of Cardiac Failure 2001, Suppl. 2, Vol. 7, No. 3, Abstract 123 

Based on the studies reviewed in section one, FDA clearance (technically referred to as 510-K clearance) was granted in 1995 for the use of EECP in angina pectoris and refractory angina. EECP was also cleared for the treatment of acute myocardial infarction (heart attack) and cardiogenic shock. EECP is not available at any of our area hospitals or emergency rooms, and we have other techniques for treating heart attack patients, but reviewing these articles and the Chinese experience with EECP in heart attack (article 3) will give us a better understanding of the power and versatility of EECP to improve coronary artery blood flow.

In the first paper, Amsterdam and associates describe the effect of EECP on patient outcome in heart attack complicated by congestive heart failure. 258 patients presenting to emergency rooms at 25 different US medical centers were randomly divided into a control group, receiving standard medical therapy, and a treatment group. The treatment group received the same standard medical therapy plus 3 hours of external counterpulsation on their first hospital day. This study was carried out in 1980, using one of the earlier external counterpulsation devices, not the sequential inflation, enhanced external counterpulsation device that we use today. In all 258 patients, the heart attack was complicated by mild congestive heart failure. In a heart attack, some heart muscle dies; if enough muscle is lost the heart will begin to fail as a pump. Blood will back up behind the heart into the lungs, producing shortness of breath and an abnormal X-Ray; we refer to this as congestive heart failure.

3.  New Sequential External Counterpulsation for the Treatment of Acute Myocardial Infarction.  Zheng-sheng Zheng et al  Thoracic Artificial Organs 8(4): 470-77, Raven Press, New York 1984 International Society of Artificial Organs

    In the US, we can treat heart attack patients with blood thinners, clot-busting drugs, angioplasty, and even urgent bypass surgery; we have the best acute-care medicine in the world. The non-industrialized nations cannot provide these services to its citizens. In China, there just aren’t the resources to treat heart attack patients with Western high technology, but you can be treated with EECP, which is the standard of care in China. Zheng’s group reports on the outcome of heart attack patients receiving 2-3 hours of EECP on their first hospital day, then one hour a day over the next five days. In China, both arm and leg cuffs are used (termed SECP), but the protocol is otherwise the same as we use in the US. Their findings are summarized below:

Effect of External Counterpulsation in Heart Attack

· Rapid relief of chest pain in 96 % of patients

· Initial EKG findings of heart attack size showed a "remarkable improvement" in 62%

·  Integrated EKG measures of heart attack size steadily improved as SECP was    continued over 7 days

· CHF and invasive hemodynamic parameters improved in 4 of 5

· Low blood pressure resolved in 17/18, shock in 5/6

· Rhythm disturbances resolved in 76%

· Hospital mortality was 5.8%

· 94.2% of heart attack patients treated with SECP and conventional supportive therapy survived their heart attack and were discharged home

When 94.2% of your heart attack patients survive their heart attack and are discharged home, you are doing a good job, whether in the US with all our technology, or in China with EECP.

 

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4.    Comparison of Hemodynamic Effects of Enhanced External Counterpulsation and Intra-Aortic Balloon Pumping in Patients With Acute Myocardial Infarction.  Taguchi, I, et al The American Journal of Cardiology 2000;86:1139-41

Katz (Physiology section – article 1), utilizing doppler ultrasound, demonstrated that EECP was just as effective as its invasive first cousin, the Intra-Aortic Balloon Pump (IABP), in augmenting diastolic blood flow within the Left Internal Mammary Artery bypass graft (LIMA).  By clinical and invasive monitoring criteria, Zheng (article 3 – this section) demonstrated the hemodynamic benefits of EECP in patients with heart attack (acute MI).  In this study, Taguchi compares EECP against the IABP in acute MI patients.  His study group consisted of 35 patients who had undergone successful balloon angioplasty for acute MI, all within 12 hours of pain onset.  

In 12 patients, Intra-Aortic Balloon Pumping was begun immediately following angioplasty, due to the finding of residual clot within the dilated artery.  In the remaining 22, EECP was carried out in the coronary care unit (CCU), 2 to 3 days following angioplasty.  All patients were maintained on heparin, an intravenous blood thinner, and no bleeding or arterial puncture site problems were encountered.  Hemodynamic measurements were taken, using indwelling pulmonary artery and radial artery pressure sensing catheters, at baseline, at various points during EECP or Intra-Aortic Balloon Pumping, and again one-hour post treatment, with the EECP cuffs off and the IABP on standby.  What did Dr. Taguchi and his colleagues find?  Is non-invasive EECP really as good as the invasive IABP?

Dr. Taguchi found that the effects of EECP and the IABP were essentially interchangeable in this group of patients, who were hemodynamically stable after undergoing urgent angioplasty to address a heart attack.  IABP lowered the systolic pressure a little more than did EECP, while EECP proved to be more effective in raising the collateral generating diastolic pressure.  Systemic vascular resistance, reflecting the resistance or “stiffness” against which the heart muscle must pump blood, fell in both groups, while the cardiac index, a measure of cardiac forward pumping function, rose with EECP but was unchanged with the IABP. 

This study, while small with respect to the number of patients treated, supports our thinking that EECP can indeed be thought of as a “non-invasive IABP”, and that it can be safely used soon after angioplasty, and that ongoing heparin anticoagulation is not a safety issue.

 

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5.    External Counterpulsation increases capillary density during experimental myocardial infarction.  Huang, W, et al  Journal of the European Society of Cardiology 1999;20(Abstract Supplement):168 

Banas, in 1973, demonstrated that EECP increased angiographically visible collateralization in patients with chronic stable angina.  In other words “new vessels" were grown, and these could be visualized on the angiogram.  Just as important may be “angiographically invisible” microcirculatory collaterals and heart muscle capillary density, indices of cardiac blood flow that we obviously cannot measure in living humans.  Amsterdam in 1980 demonstrated a 50% reduction in mortality when EECP was used to treat patients with heart attack complicated by heart failure, and the Chinese experience, using EECP as a routine treatment for MI, has been favorable, as outlined in Zheng’s ‘84  paper.  Taguchi demonstrated a vascular resistance reducing effect of EECP in acute MI patients, similar to that achieved with the IABP, so we know that a hemodynamic effect is occurring.  Could EECP rapidly enhance microcirculatory collateral flow, when applied acutely in heart attack patients? 

Looking at this issue, Huang and colleagues surgically tied off the left anterior descending (LAD) coronary artery in 14 dogs, creating a heart attack involving the front wall of the dog’s heart.  Eight dogs received 80 minutes of EECP, immediately after LAD closure, and again five hours into the heart attack.  EECP and control animals were then sacrificed at six hours, and histologic capillary density, the number of microvessels seen within the heart muscle “under the microscope”, was measured in all three layers of the heart muscle affected by the experimental heart attack.

As shown above, EECP increased capillary density within all three layers of the heart muscle.  We know that EECP provides hemodynamically effective afterload reduction in both the acute and chronic coronary insufficiency.  Angiographic and nuclear perfusion studies demonstrate an improvement in blood flow and oxygen supply in the setting of chronic angina; Huang’s study suggests that this phenomenon is also occurring when EECP is used in the treatment of heart attack.

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6.    Effect of enhanced external counterpulsation on circulating and tissue Angiotensin II in experimental myocardial infarction.  Lu, L, et al Journal of Cardiac Failure 2001, Suppl. 2, Vol. 7, No. 3, Abstract 123 

Circulating angiotensin II is our body's most potent blood vessel constrictor.  Angiotensin II within the  endothelial cells, the cells that line our arteries, is an oxidative stressor, promoting superoxide formation, nitric oxide degradation, and subsequent endothelial dysfunction, all bad things that increase our risk for arterial disease, angina, and heart attack.  The above studies showed us that EECP generates nitric oxide (a good guy) and decreases endothelin (a bad guy), so what affect will EECP have on Angiotensin II (a really bad guy)?   

Knowing that acute cardiac injury, or heart attack, is typically accompanied by a rise in angiotensin II and activation of the sympathetic-adrenal axis (our fight-or-flight response), Li and colleagues studied the effects of EECP on plasma and tissue Angiotensin II levels in the dog acute heart attack model. 

18 mongrel dogs were equally divided into three groups:  control, AMI (Acute Myocardial Infarct, the medical term for heart attack), and AMI plus EECP.  The Left Anterior Descending (LAD) coronary artery was surgically occluded in the AMI groups.  In the AMI plus EECP group, 2 hours of EECP was carried out, 1 hour following LAD occlusion.  All animals were sacrificed at three hours, and plasma, heart muscle, and aortic angiotensin II levels measured. 

As expected, heart attack activated the adrenal-sympathetic axis; circulating and tissue levels of angiotensin II rose.  EECP blunts this activation, both in the circulation and at the tissue level, in the heart muscle and within the wall of the aorta.  The afterload reducing or arterial blood vessel dilating artery effects of EECP, which we know to be comparable to that achieved with the invasive Intra Aortic Balloon Pump, may not be just mechanical (rapid cuff deflation in early systole), but biochemical, with EECP-related reductions in endothelin, and as documented in this study by Dr. Li, by a reduction in angiotensin II as well.

 

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SECTION THREE:  PHYSIOLOGIC STUDIES

The clinical benefits of EECP, the reduction in symptoms that you experience following a course of treatment, occur only because the EECP treatment has led to beneficial changes in your cardiovascular physiology.  Understanding what these physiologic changes are will help us do a better job with EECP, so this information is very important to us.  The articles in this section discuss the physiologic effects of EECP, which are:

1.  Augmentation of diastolic blood pressure, recruiting and enlarging coronary collateral vessels.  Thus blood and oxygen supply improves.

2.  Decreasing systolic pressure, "unloading" the heart, decreasing the work the heart must do to pump blood.  Thus the heart's blood and oxygen demands decrease.

3.  By increasing oxygen supply while simultaneously decreasing oxygen demand, angina improves.

4.  Left ventricular filling properties improve.  The heart is less "stiff", allowing for shortness of breath to improve.

5.  The biochemistry of your arteries, veins, and circulation improves:    

A.  Nitric Oxide, a potent vascular wall vasodilating and angiogenic chemical, is elaborated.

B.  Levels of Vascular Endothelial Growth Factor (VEGF), an angiogenic chemical (grows new blood vessels), also rise, as may the levels of other angiogenic growth factors such a Fibroblast Growth Factor, Hepatocyte Scatter Factor, and MCP-1.

C.  Levels of renin, a salt and water retaining hormone, fall.

D.  Endothelin, an undesirable, vasoconstricting chemical, decreases.

E.  Brain Natriuretic Peptide (BNP), a hormone associated with impaired cardiac filling, decreases.

F.  EECP provides an antioxidant effect

6.  Endothelial function, our most important predictor of outcome, improves.

7.  Kidney blood flow increases, improving salt and water balance.

8.  Blood flow to peripheral muscles increases, improving their physiologic status; thus your sense of overall health improves.

9.  Blood flow to all internal organs improves, explaining the non-cardiac benefits of EECP, including partial restoration of acute hearing loss and an improvement in erectile function.

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 1.  Effects of Enhanced External Counterpulsation on Internal Mammary Artery Flow:  Comparison With Intra-Aortic Balloon Counterpulsation.  Katz, WE et al. Oral Presentation 825-1, American Heath Association Meeting 3/31/98.

We are presenting EECP as a non-invasive, atraumatic Intra-Aortic Balloon Pump (IABP) like device, used over the course of seven weeks to produce a persistent improvement in cardiac blood flow. The studies cited above demonstrate that EECP works in angina and heart attack patients, with and without prior bypass, in part by transmitting an IABP-like diastolic pressure wave through the coronary arteries and/or their bypass grafts, then utilizing this pressure wave to recruit and enlarge collateral vessels.

Can EECP actually generate the same diastolic pressure as does the invasive IABP device?  Also, modern day bypass surgery utilizes chest wall artery to coronary artery bypass grafts, no longer just implanted vein grafts. (The heart ejects oxygenated blood into a large vessel called the aorta. The first vessels to be given off by the aorta are the coronary arteries, which serve the heart itself. The next set are the right and left carotids, which supply the brain. The subclavian arteries come off next, leaving the aorta at a 90° angle to supply arterial blood to the upper extremities. The left internal mammary artery arises from the left subclavian artery before it leaves the chest, and provides a blood supply to the muscles of the left chest wall. Fortunately, the chest wall is also served by blood vessels coming up from the abdomen, allowing the heart surgeon to use the left internal mammary artery (LIMA) as a bypass graft. The LIMA is left attached to the subclavian, but its end is mobilized from the chest wall muscles, and sewn into an occluded coronary artery beyond its point of blockage, bypassing the blockage. The LIMA is a very important graft, often used to bypass narrowings in the left anterior descending coronary artery (LAD), which supplies the front wall of the heart. While the average vein graft lasts seven years, nine out of ten LIMA grafts are still functional at ten years. The right internal mammary artery (RIMA) may also be used as a bypass conduit, usually to bypass a narrowing in the circumflex (CIRC).  Can EECP "turn the corner" and transmit a collateral producing diastolic pressure wave from the legs, through the aorta, around a 90° angle to the subclavian, and then through a LIMA graft to the LAD, to there grow collaterals from the LAD to a compromised vessel? Can EECP, a non-invasive device, really augment diastolic pressure as well as the invasive Intra-Aortic Balloon Pump?

To answer these questions Katz and associates used doppler ultrasound to measure the speed and direction on blood flow within the LIMA of thirteen patients (during EECP in 6 and with IABP in 7). Doppler ultrasound is similar to the radar that the state police use to catch you (well, other people, not you) speeding. A radar signal, essentially only a sound wave, is bounced off your car. The return signal is analyzed by a computer, and used to measure the speed and direction of your car. In medical doppler ultrasound a radar emitting probe is placed on the chest wall, and used to direct the radar sound wave into the LIMA. The radar sound waves bounce off the red blood cells flowing within the LIMA, and the return signal is used to determine the direction and velocity of blood flow within this vessel. In Katz’s study, doppler ultrasound was used to compare the effects of EECP and IABP on the direction and velocity of blood flow within the LIMA. Here’s what he found.

	EECP GROUP		IABP GROUP
LIMA Doppler	Velocity	VTI	Velocity	VTI
Baseline	18	6	20	6
Counterpulsation	98	19	95	15

Velocity refers to the speed, for our purposes the collateral producing thrust, of blood flow within the LIMA. VTI, the velocity-time integral, refers to the "area under the curve" or quantity of blood that flows forward with each heart beat. You can see that baseline flow parameters were similar in both patient groups. Blood flow velocity increased by a factor of five, and quantity of flow tripled during counterpulsation, both in the invasive IABP and non-invasive EECP groups.

Katz has shown that the diastolic pressure wave generated by EECP can indeed "turn the corner" and transmit a collateral producing pressure across a LIMA arterial graft. In this respect, the invasive IABP device offers no advantage over non-invasive EECP.

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2.  Pneumatic External Counterpulsation - a new Treatment for Selected Patients with Symptomatic Coronary Artery Disease. Werner et al Supplement to Circulation; American Heart Association Scientific Sessions 11/98, Abstract 1839 

Using Transesophageal doppler ultrasound, Werner measured blood flow within the Left Main coronary artery in 6 patients, before and during EECP. He found that coronary flow increased by 18% when 200 mmHg pressure was applied to the lower extremity cuffs, and by 42% when 300 mmHg was applied (Dr. Roberts’ comments: These are positive, and by themselves impressive numbers, but recall that Katz in article 1 showed us that blood flow within the Internal Mammary artery triples during EECP. It is our experience that patients with occluded vein grafts but still patent Left Internal Mammary Artery to LAD grafts respond well to EECP. It seems that EECP is particularly effective at increasing blood flow through the Left Internal Mammary bypass graft).

2a.  Left Ventricular Systolic Unloading and Augmentation of Intracoronary Pressure and Doppler Flow During Enhanced External Counterpulsation.  Michaels et al.  Circulation 2002;106:1237-42.

During EECP in the office, we measure changes in blood flow at the level of the thumb, to estimate what is going on in the aorta and coronary arteries.  Katz and Werner, in the studies abstracted above, used doppler ultrasound, either across the chest or via the esophagus, to measure EECP induced coronary artery and LIMA flow changes.  In this study, Michaels and colleagues carried out cardiac catheterization, from the wrist, in 10 individuals before and during EECP.  A catheter with a doppler ultrasound tip was used to directly measure blood pressure and flow changes in the coronary arteries and within the central aorta.  The graphic recordings obtained are truly amazing, and demonstrate the power of EECP to affect blood flow.  

The first graphic depicts central aortic pressure.  The last four waveforms are recorded off EECP; the initial 8 waveforms correspond to EECP carried out with every other heart beat.  The broken line downward arrows demonstrate diastolic augmentation, the coronary artery perfusing, diastolic pressure wave generated during external cuff compression.  Notice how the native systolic waveforms that follow external cuff inflation, the assisted beats (short bold arrows) are lower than the systolic waveforms not preceded by EECP.  This reflects afterload reduction, the reduction in systolic pressure, and hence cardiac workload, that occurs during EECP.  

The 2nd graphic depicts blood flow within a coronary artery that is not blocked; an artery from which we want to generate collateral vessels.  The bold downward arrows represent systolic flow and the broken downward arrows depict diastolic flow.  Remember that the heart obtains 80% of its oxygen and nutrition during diastole.  Also recall that we are attempting to create a pressure gradient, during diastole, between an open and a blocked coronary artery, to encourage sideways or collateral flow from the open to the blocked artery.  Diastole is thus our "window of opportunity" to help the diseased heart.  The first complex is pre-EECP.  The cuffs are then activated and the following 10 beats demonstrate a progressive, mild decline in systolic flow, and a progressive, large increase in diastolic flow; net coronary artery blood flow increases markedly.  The augmented diastolic flow reflects an improved cardiac oxygen supply during the EECP treatment, and of greater importance, an increased pressure gradient between the unblocked, collateral donating vessel,  and the blocked vessel to which we want to generate and enlarge collateral arteries.

The 3rd graphic depicts flow within a normal coronary artery, initially at baseline, than during EECP carried out at low pressure, and then during EECP carried out with gradually increasing external cuff pressure.  You can see that an increase in external cuff pressure is mirrored by a corresponding increase in coronary artery diastolic pressure.  This is why we "squeeze you" so hard.  Your legs may ache a little, but this is a minor inconvenience to obtain a remarkable health benefit.

 

Regardless of the measuring tool, it is clear that EECP, a non-invasive therapy, is producing great changes in the degree and pattern of blood flow in the coronary arteries and aorta, and this plays an important role in EECP's positive clinical effects.

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3.  Blood Pressure Changes During External Counterpulsation.  Werner et al European Heart Journal 1998;19(Abstract Supplement) P 3659(655). 

         The point, or physiologic basis for EECP, is its ability to:

A.  Increase diastolic pressure, forcing open, and then dilating coronary artery collateral vessels, 

and

B.  Lower systolic blood pressure, "unloading" the heart, thus decreasing the heart's workload and consequently its need for blood and oxygen.  

So how much are we really increasing diastolic blood pressure? We know that EECP is as effective as the invasive Intra-Aortic Balloon Pump at increasing coronary artery and LIMA diastolic flow, but just what is the effect of EECP on the patient’s systolic and diastolic blood pressure? How much does it go up or down during EECP? Werner’s group measured blood pressure, before and during EECP in normal volunteers and angina patients.  Here’s what they found:

	BP at Rest			BP during EECP
Group	Syst.	Diast.	Mean	Syst.	Diast.	Mean
Volunteers	133	72	89	120	140	95
Coronary	124	62	81	126	154	102
Combined	123	64	81	120	137	95

 

Recall that the point of EECP is to increase blood flow to the coronary arteries in diastole, without increasing the systolic pressure. An increase in systolic blood pressure would increase the heart’s workload and would not improve coronary blood flow - this would worsen the patient’s angina. Thus we want to see high diastolic and lower or at least unchanged systolic values, and that is what we get with EECP. In the coronary patients, the collateral producing diastolic pressure rose from 62 to 154 mmHg. Systolic pressure was essentially unchanged.* Systolic values actually fell in the normal volunteers.  Sometimes patients are concerned that EECP will generate dangerously high pressures, placing them at risk for stroke. You can see that this did not occur in Werner’s patients.

* Even though the recorded systolic pressure may not change, the heart is still rested during EECP. The explanation is a little technical. Rapid deflation of the leg cuffs creates a sort of vacuum in the aorta, by itself lowering the systolic blood pressure. But the heart is now ejecting blood against less aortic resistance, so it can eject the blood more forcefully, while not working very hard. This increased force of blood ejection tends to raise the systolic pressure. Whether your systolic blood pressure stays the same or falls depends on the balance between these two forces. Either way, during EECP your heart performs better while working less. When your heart is not working as hard, it needs less oxygen, and when your heart needs less oxygen, then your angina improves.

 

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4.  Improvement of Renal Perfusion and Function by Pneumatic External Counterpulsation.  D. Werner et al European Heart Journal 1998;19(Abstract Supplement)  P3660(655).  

How does EECP effect the kidneys? Will EECP improve or compromise blood flow to the kidneys? What happens to kidney function? These are important questions, as many of our patients with recurrent coronary disease also have impaired kidney function. In these patients, the X-ray dye that we use during angiography and angioplasty can sludge up in the kidneys, compromising kidney function further; full blown kidney failure can rarely occur. In this group, we might turn to EECP as a safer means of reducing angina, but we need to be sure that EECP also won’t harm the kidneys. Intuitively, one would predict that EECP would have a beneficial effect on kidney function. The American studies discussed above show that EECP increases blood flow to the heart and improves heart function. Blood flows through native arteries, vein grafts, and arterial grafts increases, and heart function, as measured by treadmill time, nuclear scanning, and angina frequency, also improves. Chinese studies tell us that blood flow to the brain increases with EECP, leading to an improvement in brain function in certain patients. Werner and colleagues set out to study the effect EECP has on blood flow to the kidneys and how this might affect kidney function.

Using a non-invasive ultrasound technique, Werner measured blood flow to the kidneys before and during EECP in 9 healthy volunteers. Parameters of kidney function were assessed in 12 others. Their findings are summarized in the table and discussed below:

Parameter	Pre-EECP	During EECP	% Change
Kidney Blood Flow	522 ml/min	676 ml/min	+ by 21%
Sodium Excretion	0.18 mmol/min	0.35 mmol/min	+ by 94%
Chloride Excretion	0.1 mmol/min	0.22 mmol/min	+ by 120%
Urine Production	3.3 ml/min	5.3 ml/min	+ by 60%
Renin	4.4 pg/ml	3.2 pg/ml	¯ by 37%
Endothelin	9.5 pg/ml	7.5 pg/ml	¯ by 27%

 

A. Blood flow to the kidneys increased by 21%, from 522 to 676 ml/min. This is a positive finding. The more blood presented to the kidney per minute, the better it can do its job of filtering waste products and controlling body water and salt levels.

B. One of the jobs of the kidney is to remove salt from the body, so excretion of the components of salt, sodium and chloride, serve as a measure of kidney function. During EECP, sodium excretion nearly doubled, from 0.18 to 0.35 mmol/min; chloride removal increased likewise from 0.1 to 0.22 mmol/min.

C. Urine is composed of body wastes, byproducts of metabolism that have toxic effects if allowed to remain in the body. The kidney filters these waste and excretes them in the urine, so urine production rate serves as a good measure of overall kidney function. Werner found that urine production increased by 60% during EECP, from 3.3 to 5.3 ml/min. This is why you feel the need to empty your bladder during EECP - because your kidneys are working better.

D. Renin is a kidney produced hormone that plays a key role in salt and fluid balance and blood pressure control. When renin levels are high, sodium and water are retained, and blood pressure rises. When renin levels are low, sodium and water are excreted, and blood pressure falls. When blood flow to the kidneys is impaired, the kidneys will produce more renin. Salt retention will occur, expanding the blood volume. Blood pressure will rise, increasing blood flow to the kidneys. Blood flow to the kidneys and kidney function will improve, but the rest of the body pays a price. The elevation in blood pressure strains the heart and increases the patient’s risk of stroke. The salt and water retention may lead to edema formation or an aggravation of congestive heart failure. When it comes to renin production, the kidney "cares only about itself". This is why patients with poor kidney function or impaired blood flow to the kidneys as a result of cardiovascular disease typically have elevated renin levels, high blood pressure, and a tendency towards fluid retention, edema, and congestive heart failure. On the other hand, when the kidneys are receiving an adequate blood flow, they begin to produce less renin, and good things follow. Blood pressure falls, decreasing stroke risk and the heart’s workload. With less fluid retention comes an improvement in edema and a decreased tendency towards CHF. For the cardiac patient, an elevated renin level is bad, and any intervention that lowers renin is to their benefit. During EECP, renin levels fell by 37%, from 4.4 to 3.2 pg/ml.

E. Endothelin is nasty stuff. It constricts arteries. It constricts the coronary arteries, compromising blood flow to the heart. It constricts peripheral arteries, raising blood pressure, increasing the heart’s workload. We want a low endothelin level, especially if we have coronary artery disease. Werner found that endothelin levels fell by 27% during EECP, from 9.5 to 7.5 pg/ml.

To summarize, in healthy volunteers (and presumably in patients), EECP:

1.  Increases blood flow to the kidney

2.  Improves the ability of the kidney to produce urine

3.  Promotes excretion of sodium and chloride

4.  Lowers levels of the harmful hormones renin and endothelin

 

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5.  Pneumatic External Counterpulsation:  A New Noninvasive Method to Improve Organ Perfusion.  Werner, D, The American Journal of Cardiology 1999;84:950-52     

In China, EECP is not confined to the treatment of coronary insufficiency.  Stroke, cerebrovascular insufficiency, hepatitis, and even diabetes have been addressed with external counterpulsation with measurable benefits.  Why should this be?  We know that all of these disease states involve free radical tissue damage.  Dr.Quan, in article 7, is going to show us that EECP has a significant antioxidant effect.  EECP increases blood flow to the coronary arteries that serve the heart.  Could an increase in blood flow, with an attendant increase in oxygen and fuel supply to the diseased organ be a mechanism of benefit?  Werner and colleagues set out to measure the effect of EECP on blood flow to different organ systems.  They used doppler ultrasound (as in Dr. Katz's study - article 1) to measure blood flow per heart beat at rest, during EECP using calf and thigh cuff inflation, and during EECP using calf, thigh, and lower abdominal/pelvic cuff inflation (the method we use in the US).  Here's what they found:

200 mm Hg pressure - calves and thighs
ARTERY	% INCREASE IN FLOW
Left Main Coronary ( Heart )	18 %
Carotid Artery ( Brain )	19 %
Vertebral Artery ( Brain )	12 %
Hepatic Artery ( Liver )	25 %
Abdominal Aorta ( Pelvis & Legs )	88 %
Renal Artery ( Kidney )	21 %
Internal Iliac ( Leg )	144 %
Stroke Volume ( Flow leaving the Heart )	12 %
300 mm Hg - calves, thighs, & pelvis
ARTERY	% INCREASE IN FLOW
Left Main Coronary ( Heart )	42 %
Internal Carotid ( Brain )	26 %

EECP increases blood flow everywhere, not just to the heart.  Organ dysfunction present on the basis of reduced blood flow could thus improve during EECP.  In China, arm cuffs are utilized, further increasing blood flow to the brain, and in this fashion EECP is used in the treatment of stroke.  This ability of EECP to improve blood flow in general may lead to some additional applications of EECP in this country - research is ongoing and much more is planned.        

 

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6.  Pneumatic External Counterpulsation - a new Treatment for Selected Patients with Symptomatic Coronary Artery Disease. Werner et al Supplement to Circulation; American Heart Association Scientific Sessions 11/98, Abstract 1839 

Werner provided EECP to 13 patients with refractory angina.  As in our other studies, angina frequency and NTG needs were recorded. Treadmill nuclear scans were carried out before and after EECP.  Unique to this study, in 9 patients Vascular Endothelial Growth Factor (VEGF) levels were measured, pre and post-EECP. VEGF is a growth factor, a hormone like substance that promotes angiogenesis, the growth of new blood vessels. We make a lot of this stuff when we are young and developing, but not very much as we age. It would certainly be desirable to have high levels of VEGF if we have an occluded coronary artery. Presumably, VEGF will promote the development of collateral vessels. Genentech (the biotech firm that manufactures TPA, the clot dissolving agent that we give you to reverse a heart attack), has found a way to manufacture VEGF. Research is being carried out now to see if intracoronary injection of VEGF will be of value to coronary patients. So what effect, if any, will EECP have on VEGF levels? Let’s look at Werner’s findings.

For the group, angina frequency fell from 6.4 to 3.3 episodes per week; NTG use decreased from 5.5 to 2.7 tablets a week. Exercise capacity, as assessed by treadmill level, increased by 19%, from 117 to 137 watts; nuclear scan findings also improved. In the 4 patients whose angina did not decrease by ³ 50%, VEGF levels did not change significantly. However, in the 5 patients who experienced a ³ 50% reduction in angina, VEGF levels increased by 21%, from 110 to 133.

Collateral generation due to EECP has always been considered to be a physical phenomena, where the augmented diastolic pressure wave forces open new collateral vessels. It may be that EECP is also producing a biochemical phenomena, increasing VEGF levels and encouraging the new growth of blood vessels. Conversely, it may be that an increase in VEGF is simply the consequence of an increased collateral flow. Further research will answer these questions. Who knows, in the future we may be injecting VEGF into patients immediately pre-EECP to get a combined effect.

6a.  Vascular Endothelial Growth Factor and Atrial Natriuretic Peptide in Enhanced External Counterpulsation.  Kho, J, et al.  Endocrine Society's 82nd Annual Meeting 2000, 6/21 Poster Board 76, Abstract 561.

To confirm Werner's findings, Kho recorded VEGF levels at various time points in 11 patients receiving EECP for persistent angina.  VEGF levels rose for the group, as depicted below.  Kho and associates did not attempt to correlate the rise in VEGF with the clinical response of each patient, but they did note a great deal of variability amongst the patients, in terms of the magnitude and time-course in their individual VEGF increases.  Right now our feeling is that a rise in VEGF is a therapeutic consequence of EECP, and a cause of angiogenesis. 

 

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7.  Effect of Enhanced External Counterpulsation on Lipid Peroxidation in Coronary Disease.  Xiao-Xian Quan et al 1^st International Congress on Heart Disease - New Trends in Research, Diagnosis, and Treatment. The Journal of Heart Disease 1:1 May ’99.

We know that antioxidant vitamins provide both short and long term benefits to coronary disease patients. For example, the Indian Experiment of Infarct Survival demonstrated that antioxidant therapy begun in the emergency room reduced heat attack size and lessened 30 day post heart attack mortality by a third. The British CHAOS study randomized 2000 patients with abnormal angiograms to receive either vitamin E or an inert placebo. The study was randomized and double-blind (neither the investigators or the patients knew which treatment they were receiving), eliminating any form of bias. Two years out, the vitamin E group enjoyed a 77% reduction in heart attack rate. Both antioxidants and EECP seem to have a favorable effect on outcome, so the question comes up, could EECP have an antioxidant effect?

We know that coronary patients experience a higher level of oxidative stress than do healthy individuals - in other words, their antioxidant defenses are impaired. Oxidative stress damages the cholesterol molecule, making it much more likely to layer out in our arteries as plaque. Malondialdehyde is generated when our cell membranes are damaged by abnormal oxidative stress. Vitamin E lowers the malondialdehyde level, while cigarette smoke will increase it. Malondialdehyde levels tells us who is winning the war, the oxidative stressors that are trying to plug up your arteries, or the antioxidant defenses that are trying to keep you free of coronary disease. A treatment that lowers malondialdehyde levels is exerting an antioxidant effect, just like vitamin E, and thus should have a beneficial effect on outcome.

Xiao-Xian and colleagues measured malondialdehyde levels in 35 healthy volunteers, and in 69 coronary patients at various points in their treatment. At random, 31 of the patients were assigned to treatment with EECP, and 38 to drug therapy alone. Here's what Dr. Xiao-Xian and his colleagues found:

Pre-treatment malondialdehyde levels were similar in both patient groups, and as expected, were well above the average value of the normal volunteers. Drug therapy had no effect on the malondialdehyde level. We expect this. Drugs are drugs; they decrease symptoms but do not affect the abnormal chemistry that wants to plug up your arteries. In the EECP group, malondialdehyde levels fell steadily as the patients progressed through their 35 hour EECP program. Like standard drug therapy, EECP decreases symptoms, but unlike drug therapy, EECP also affects your body chemistry. EECP lowers malondialdehyde levels and thus has an antioxidant effect, just like vitamin E. This antioxidant effect of EECP helps to explain its favorable effect on long term outcome. Could EECP have an effect on other important biochemical factors?

 

 

 

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8.  Effect of Enhanced External Counterpulsation on Nitric Oxide Production in Coronary Disease.  Xiao-Xian Quan et al 1^st International Congress on Heart Disease - New Trends in Research, Diagnosis, and Treatment. The Journal of Heart Disease 1:1 May ’99.

The cells lining our arteries, termed endothelial cells, convert arginine, a dietary amino acid, into nitric oxide. The job of nitric oxide, also known as endothelial derived relaxing factor, is to preserve normal artery function and protect against the development of vascular disease. Nitric oxide strengthens the arterial lining, making it more resistant to cracking, clotting, and spasm. Cigarette smoke and other oxidative stressors will inactivate nitric oxide, while antioxidants and supplemental arginine will increase its production. Animal studies have shown arginine to be more effective than Mevacor, a prescription cholesterol lowering agent, in reversing diet induced vascular disease. Human studies have shown arginine, taken either oral or IV, to be effective in controlling effort induced angina, vasospastic angina, hypertension, heart failure, and small vessel disease (see The Arginine Solution by Drs. Fried and Merrell). Any treatment that increases nitric oxide should have a favorable effect on angina severity and long term outcome. What effect will EECP have?

Dr. Xiao-Xian measured nitric oxide levels in healthy volunteers, and in coronary patients at various points during drug or EECP therapy, using the same protocol as in the malondialdehyde study reviewed above. 

As expected, baseline levels of nitric oxide were well below normal in both patient groups. During drug therapy, the average nitric oxide level rose only slightly, while a dramatic, steady increase occurred during EECP. The end EECP level was well above that of the normal volunteers. Shearing stress on the lining of our arteries, such as occurs when blood flow increases during exercise, seems to be a potent stimulator of nitric oxide production. The rhythmic compression of EECP produces a similar shearing stress, and we feel this exercise-like effect of EECP is responsible for its beneficial effect on nitric oxide levels. Whatever the mechanism, we like the result. We are starting to appreciate that EECP does more than just physically open collaterals. EECP exerts definite beneficial effects on our biochemistry, and here the research is just beginning to scratch the surface.

 

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9.  A Neurohormonal Mechanism for the Effectiveness of Enhanced External Counterpulsation.  Wu, Giu-Fu et al  Circulation 100:18; Suppl. 1 Abstract 4388 1999    

Xiao-Xian and his colleagues, working in China, have shown us that EECP provides both antioxidant and nitric oxide generating effects.  Werner's group, working in Germany, demonstrated that Vascular Endothelial Growth Factor, an angiogenic, or new blood vessel promoting factor, rises as well, and that levels of renin, a deleterious salt retaining and vasoconstrictive hormone, will fall.  These biochemical effects helps to explain why EECP has a positive effect on long term, not just short term, patient outcomes.  

Endothelin, another angiochemical that is produced by the endothelial cells that line our arteries, promotes both blood vessel constriction and plaque deposition.  Endothelin seems to be the most important antagonist of nitric oxide and good vascular health, sort of the Darth Vader of angiochemicals.  What effect will EECP have on endothelin levels - will they fall, just like renin does?  Is there a relationship between a fall in endothelin and the rise in nitric oxide?

To answer these questions, Dr. Wu and his associates measured nitric oxide and endothelin levels in 43 angina patients, before, after, and at various points during a 36 session course of EECP.  There data answered a question that had been puzzling me.

I've noticed that some patients begin to feel better by Friday of their first week of EECP.  This never made sense to me - there's no way that we could be growing collaterals that quickly.  We're not, but what Dr. Wu is showing us is that nitric oxide levels rise, and just as importantly, that endothelin levels fall, following the very first treatment.  When you take a nitroglycerin tablet, you are giving your body a shot of nitric oxide as a drug effect - your angina resolves and you feel better.  With EECP, we are teaching the body to make its own nitroglycerin, nitric oxide, and to stop producing the plaque promoting vasoconstrictor, endothelin.  This trend continues throughout the entire course of treatment.  Nitric oxide continues to rise, endothelin falls, as does the endothelin to nitric oxide ratio.  One and three months post-EECP nitric oxide begins to fall off and endothelin is seen to rise, but the levels remain improved from the patients pre-treatment baseline.  The message here is that EECP doesn't just grow collaterals, EECP produces an improvement in your vascular biochemistry, and it does so rapidly.

    

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10.  Intermittent Shear Stimuli by Enhanced External Counterpulsation (EECP) Restores Endothelial Function in Patients with Coronary Artery Diseases.  Urano, H, Circulation 102:18 Suppl. II Oct. '00

“As goes the endothelium, so goes the patient” is a scientifically correct statement.  The endothelium refers to the thin layer of cells that line our arteries and veins.  These cells are essentially tiny hormone and angiochemical producing factories.  They make the “good guys”, nitric oxide and VEGF, which promote vascular wall integrity, blood vessel vasodilation, and the growth of new vessels.  The endothelium also makes  “bad guys”, such as endothelin, which promotes vasoconstriction, abnormal clotting, and plaque deposition.  Endothelial health determines whether the good guys or bad guy angiochemicals will dominate, and has been shown to be a key indicator of cardiovascular health and long-term outcome.  We can accurately assess endothelial health by measuring brachial artery flow mediated vasodilation.  Here we measure the diameter of the brachial artery (the major artery to the arm at the level of the elbow), before and after release of a blood pressure cuff, which had been inflated enough to impair flow to the forearm for five minutes.  As blood flow is restored to the forearm, the brachial artery will dilate by 10-12% to accommodate this increased flow, if endothelial function is normal.  If endothelial function is mildly impaired, flow mediated vasodilation will be less than 10%.  In patients with established cardiovascular disease, or risk factors for cardiovascular disease such as hypertension, smoking, or high levels of homocysteine or LDL cholesterol, endothelial function may be severely impaired, and the brachial artery will actually constrict.  Indeed, endothelial dysfunction may be a final common pathway through which many of the causes or cardiovascular disease actually cause cardiovascular disease.  Multiple studies have shown that the health of the endothelium at a given point in time is a critical determinant of the cardiovascular health and vital status of the patient 2 to 5 years later.  Whether we are looking at patients with angiographically normal coronary arteries and spasm, individuals with non-obstructive atherosclerosis, or patients with obstructive multi-vessel disease, those with preserved endothelial function do well, while those with impaired endothelial function at baseline are at increased risk for a future adverse cardiac event.  The worse the endothelial function, the greater the likelihood that an event will occur.  So far, treatments that improve endothelial function have been shown to improve outcome.  Accupril, a prescription agent, improves endothelial function by blocking endothelial bound ACE, a nitric oxide degrader.  Accupril decreases restenosis after angioplasty or stent placement, and the QUO VATUS study showed us that Accupril decreases one-year post-CABG event rate by 80%.  Vitamin E blocks endothelial superoxide, another nitric oxide degrader; the CHAOS study demonstrated that vitamin E, begun after angiography, reduced two year event infarction/death rate by 47%.  During exercise blood flow velocity and quantity increase, exerting a radial shearing stress on the endothelium.  A healthy endothelium, and to a somewhat lesser extent an unhealthy endothelium, will respond by elaborating more nitric oxide.  Nitric oxide will in turn improve endothelial function, dilating the vessel to accommodate the increased flow, and will promote collateral generation.  Exercise leads to an increase in nitric oxide and multiple studies have shown that regular exercise improves outcome – this is why cardiac rehab programs are so helpful.

EECP certainly improves the outcome of coronary patients, and EECP certainly increases the velocity and quantity of blood flow, not just in the coronaries but also within every vascular bed in the body.  We know that EECP increases nitric oxide and VEGF and decreases endothelin levels, so the logical question is – Can EECP improve endothelial function?

To answer this question, Urano measured flow mediated brachial artery vasodilation, a reproducible, accurate measure of systemic and coronary endothelial function, before and after a 35-hour course of EECP, given to stable angina patients with documented coronary disease and abnormal stress EKG studies.  The patients’ clinical status and treadmill findings improved, consistent with all prior studies.

  

Flow mediated brachial artery vasodilation, significantly impaired at baseline at 4%, improved 3-fold following EECP to 12%, essentially a normal value.  It’s becoming clear that EECP decreases symptoms and improves outcome not just by forcing open collaterals, but also by improving the patient’s biochemistry and endothelial function.  It hasn’t been studied yet, but it is my impression that measures designed to improve endothelial function, such as tissue specific ACE inhibitors, arginine, omega-3 essential fatty acids, and anti-oxidants, improve and extend the patient’s response to external counterpulsation.  These agents all have beneficial effects on their own, so now I typically place new EECP patients on an “endothelial cocktail” of these treatments, and continue it post-EECP.  

10a. Endothelial function in patients with severe coronary artery disease treated with enhanced external counterpulsation (ECPT).  Schechter, M, et al.  European Heart Journal (2002) 23 (Abstract Supplement) - P2363, page 463. 

Urano's study, abstracted above, demonstrates that EECP restores endothelial function in patients with coronary insufficiency, certainly a good thing; his study was carried out in Japan.  In this paper, Schechter and colleagues repeat Urano's study, here in an Israeli population of inoperable coronary patients with persistent class 3 to 4 symptoms.  Their normal range was not given, and may be different from Urano's (different researchers may use different measuring techniques so their "normal" values may be different), but in Schecter's population, just as in Urano's, percent flow mediated vasodilation, the measure of endothelial tone, increased with external counterpulsation, here from 3.5 to 8.2%, coincident with a reduction in average NTG need from 4.7 to 0.4 tabs per day, and an improvement in functional class from 3.3 to 2.0. No matter which continent you use it in, or what you call it (EECP in the US, Asia, and Europe or ECPT in Israel), external counterpulsation works.  Endothelial function, the critical predictor of cardiovascular health and outlook, improves, while previously treatment refractory symptoms recede or resolve.  

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11.  The New Therapeutic Approach with the Enhanced External Counterpulsation in Patients with Chronic Stable Angina:  Evaluation of Myocardial Flow and Flow Reserve by N-13 Ammonia Pet.  Masuda, D, Circulation 100:18 Suppl. 1 Nov. '99

Our most precise indicator of coronary artery blood flow is the PET (Positron Emission Tomography) Scan.  Here the scan measures not only blood flow, but the metabolic function of the heart muscle cells supplied with blood and oxygen by a given coronary artery.  Dr. Masuda recorded coronary artery flow reserve by the Dipyridamole PET technique, nitric oxide levels, and treadmill time in 11 patients undergoing a 35 hour course of EECP.  

Treadmill time improved by 49 seconds, or 12%, from 390 to 439 seconds.  Time to ST depression, the EKG event reflecting insufficient blood flow to the exercising heart muscle, increased by 185 seconds, essentially doubling, from 190 to 375 seconds.  Nitric oxide level doubled, and regional perfusion, the PET indicator of collateral generation, increased in all vascular distributions studied. 

With EECP, collateral vessels are recruited and enlarged, nitric oxide and antioxidant levels rise, renin and endothelin levels fall, PET, Thallium, and stress EKG findings improve, angina decreases and patients feel better.  

EECP is getting the job done!  

 

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12.  Pneumatic External Counterpulsation (PECP):  A New Treatment Option for Therapy-Resistant Inner Ear Disorders?  Offergeld, C, Werner, D, et al Laryngo-Rhino-Otologie – Otologie  Abstract L-R-O 9 

 In Germany, the standard therapy for sudden deafness and tinnitus (persistent ringing in the ears) involves drug therapy designed to improve blood flow to the inner ear.  Werner’s group had previously demonstrated an increase in carotid artery blood flow with EECP (described in Germany as PECP).  In this study, 30 patients with acute hearing disorders and/or tinnitus, persisting despite standard drug therapy, received 5-10 one-hour EECP treatments.  For the group, internal carotid (front of the brain) and vertebral artery (back of the brain) flow volume, measured by doppler ultrasound, increased during EECP by 19% & 11% respectively.  Tinnitus decreased in 47% of the patients, by an average of 16 dB.  Hearing threshold increased in 28%, on average by 19dB.  Audiometry studies carried out post-treatment demonstrated that the improvement related to EECP persisted throughout a one-year follow-up period.  Sudden hearing loss, in certain cases, appears to be related to a reduction in blood flow to the ear and/or the nerves that connect it to the brain.  EECP has the potential to increase blood flow to any organ, and to permanently enhance flow via collateral formation.  It makes sense that EECP would help here.

   

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13.  Enhanced External Counterpulsation as a New Treatment Modality for Patients with Erectile Dysfunction.  Froschermaier, S, Urologia Internationalis 1998;61:168-71

Erectile Dysfunction (ED) is essentially endothelial dysfunction, here compromising nitric oxide production and consequent vasodilation within the penile arteriolar system.  Viagra works by blocking the breakdown of cGMP, nitric oxide’s second messenger, so it stands to reason that measures designed to improve penile endothelial function will help with ED.  Arginine supplementation improves overall and penile endothelial function, and helps when ED is vascular in origin.  Several papers have documented the nitric oxide generating feature of EECP, and Urano’s paper (article 10 – this section) showed us that vascular endothelial dysfunction, as measured by flow mediated brachial artery vasodilation, essentially normalizes following a course of treatment.  We know from Werner’s paper (article 5 – this section) that blood flow to the pelvic region (internal iliac artery) increases by 140% during an EECP treatment, so we can predict that EECP might be helpful in ED.  Fricchione’s study (article 5 – section 1), which focused on the effect of EECP on quality of life parameters, noted that love life improved in 1/3 of their subjects following EECP.  In this paper, Froscheimer studied the effects of EECP on both subjective and physiologic parameters of erectile function in 13 men with ED. 

  All 13 men had a stable sexual relationship.  6 of the men were diabetic and  12 were cigarette smokers.  Physiologic and functional measurements of erectile function were carried out before and 4 weeks after a standard 35 hour course of EECP.  Each man graded the quality of erectile function on the following 4-point scale,

E0 = No erection	E1 = Poor erection, immediate loss
E2 = Soft erection, but adequate for sex	E3 = Full erection

and recorded the percentage of attempts at intercourse that were successful.  As a physiologic measure, peak penile artery blood flow rate was recorded.  Froschermaier’s findings are presented below is tabular and graphic form.   

	Peak Systolic Flow	Quality of Erection
Before EECP	0.32 cm/s	1.5
After EECP	0.60 cm/s	2.3

Penile artery systolic flow essentially doubled, and perceived quality of erection on a four-point scale improved from 1.5 to 2.3.  Pre-EECP, intercourse was not possible for 7 of the men, and was successful in <20% of attempts in 6.  Only 2 of the 13 men did not benefit from EECP; erectile dysfunction improved in 7, while in 4 ED fully resolved.  Only 3 of the 13 subjects reported spontaneous morning erections pre-EECP, while post-EECP 11 men noted morning erections.  Patients come to us for relief of refractory angina, but they don’t mind it a bit when their love life improves. 

 

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 14.  Enhanced External Counterpulsation Improves Exercise Tolerance, Reduces Exercise-Induced Myocardial Ischemia and Improves Left Ventricular Diastolic Filling in Patients With Coronary Artery Disease.  Urano, H, J Am Coll Cardiol  2001;37:93-9

This study looked at the effect of EECP on diastolic dysfunction (impaired cardiac filling in-between beats or “stiffness”), and its hormonal marker, brain natriuretic peptide.  Here Urano and colleagues carried out  stress EKGs, same distance stress thallium perfusion scans, resting MUGA scans (which measures cardiac filling or diastolic function), and measured natriuretic peptide levels in 12 coronary patients before and after a 35 hour program of external counterpulsation.  

Treadmill time increased by 29%, time to ST depression (the EKG sign indicating that blood and oxygen supply is not meeting demand) by 23%, and peak exercise level achieved by 20% - no surprises here.  The same distance stress thallium findings improved, as expected, with a 45% decrease in reversible perfusion defects (reversible defects indicate impaired flow to viable heart muscle while fixed defects indicate a prior heart attack). 

Regarding diastolic function, the left ventricular end-diastolic pressure, which reflects “stiffness” of the heart, fell from 12 to 9 mmHg.  Peak filling rate and time to peak filling rate improved by 13% and 20% respectively, and correlated with a 14% reduction in brain natriuretic peptide level (BNP).  Brain natriuretic peptide is secreted from the left ventricle in response to wall stress or stretch.  BNP rises in the presence of diastolic (filling) and/or systolic (pumping) dysfunction, and at this point serves as our most accurate hormonal marker for congestive heart failure (CHF).     

  This paper tells us that EECP improves diastolic function and lowers BNP levels, as it improves myocardial perfusion.  This helps to explain the beneficial effect of EECP in heart failure, which we will examine in section four.

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 15.   Enhanced External Counterpulsation with heparin pre- treatment improves exercise capacity of anginal patients.  Fujita, M, Coronary Artery Disease Abstract Book, Lyon France 2000; October: 469.  

My feeling is that measures designed to enhance nitric oxide production and endothelial function will enhance and extend the patient’s response to EECP.  Fujita and colleagues, citing prior work which demonstrated that treadmill parameters, nuclear stress scan findings, and angiographic collateral score improve significantly more when intravenous or subcutaneous heparin are administered prior to exercise in patients undergoing cardiac rehab, hypothesized that heparin pre-treatment might enhance one’s response to EECP.  In this study, fifteen angina patients received a standard 35-hour course of EECP; in five, 5000 units of IV heparin was administered 10-20 minutes pre-EECP.  Treadmill time and maximum exercise double-product increased in all 15.  Fujita’s findings are at present available only in abstract form and numbers were not included, but he states that the extent of improvement in the treadmill parameters was much greater in the heparin-EECP combined therapy group.  Dipyridamole PET assessment of myocardial flow reserve also improved more in the patients pre-treated with heparin.  We think of heparin as an anticoagulant, or blood thinner, but heparin also stimulates the release of angiogenic growth factors, specifically fibroblast growth factor (FGF) and hepatocyte scatter factor (HSF).  All of these growth factors, and undoubtedly more that remain to be discovered, are important in angiogenesis, the generation of new blood vessels that is one of the goals of EECP.  Combining the nitric oxide, VEGF, and endothelial function benefits of EECP with the stimulation of FGF and HSF from heparin, an additive or synergistic effect on patient outcome is expected – exactly what Fujita found in his patients.  A formal American study of EECP alone vs. EECP preceded by IV heparin vs. EECP preceded by subcutaneous Enoxaparin (a heparin derivative) has been proposed  Our goal is to find means of further improving the efficacy of EECP, without adding risk or significant cost to the procedure, and we are optimistic that pre-treatment heparin will be of value.    

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        16.   Enhanced External Counterpulsation Promotes Angiogenesis Factors in Patients with Chronic Stable Angina.  Masuda, D, et al.  Circulation 2001 II-445 Abstract 2109. 

          We've learned that EECP increases VEGF levels - elaboration of this angiogenic factor is one of the reasons that EECP works.  Extending this concept, Fujita and colleagues, in the study abstracted above, demonstrated that pre-EECP heparin would increase the levels of two other growth factors, Fibroblast Growth Factor (FGF) and Hepatocyte Scatter Factor (HSF), improving our ability to provide angiogenesis, and thus a better coronary blood supply, with EECP.  In this study Masuda and colleagues looked at the effect of EECP on a number of angiogenic growth factors.

          Eleven patients with angina underwent a standard, 35-hour course of EECP.  Blood levels of several angiogenic growth factors (VEGF, FGF, HSF, and MCP-1) were obtained before and following the course of EECP treatment.  The average increase in the four growth factors in this group of eleven angina patients is shown below:

                                                                                                                                                                  Recall that Dr. Werner (article 6 - this section) found that VEGF levels did not rise in patients who did not experience a > 50% reduction in angina with EECP, but that the levels rose by 21% in patients who did.  Masuda did not give outcome data, but the average 16% increase in VEGF following EECP in his patients in Japan corroborates Werner's findings in Germany.  HSF and FGF levels rose by 27% and 19%, respectively, and capitalizing on Fujita's work, if we pre-treat our patients with Heparin, we would anticipate an even better response.  Average MCP-1 levels did not rise, and we don't know how to manipulate this growth factor pharmacologically (but  give us time and we will).

          

                                                                                                                                                                         This chart shows the percentage of patients that demonstrated a rise in each growth factor.  Notice that the response is non-uniform; 2/3rds of the patients demonstrated an increase in HSF and FGF, while only 1/3rd increased their VEGF and MCP-1 values.  Why does this occur, and can we do anything about it?  Likely, we differ in our ability to create growth factors, in response to EECP, exercise, or other angiogenic stimuli.  The differences may be genetic, or perhaps co-existent disease states block our ability to make our own growth factors.  Research here is ongoing, but for now we will utilize the science that Werner, Fujita, and Masuda have given us - if the patient wishes, or if feel that they will need the assist, we can pre-treat them with Heparin prior to each EECP session (I have not formally compared EECP treatment outcomes, with or without Heparin, in my own patients, but my impression is that the Heparin is helping.  When our patients finish EECP and move on to Cardiac Rehab or an exercise program, we often keep them on Heparin; here they self-administer a dose 10-20 minutes before exercising.  Heparin can be absorbed under the tongue.  This is obviously easier on the patient and certainly less expensive than Heparin by injection; several patients have taken Heparin by the under-the -tongue, sublingual approach and this seems to be working well).

 

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SECTION FOUR:  CLINICAL STUDIES - HEART FAILURE        

Enhanced External Counterpulsation as Treatment for Chronic Angina in Patients with Left Ventricular Dysfunction:  A Report From the International EECP Patient Registry (IEPR).  Soran, O, et al.  CHF 2002;8:297-302    

Efficacy and Safety of Enhanced External Counterpulsation in Mild to Moderate Heart Failure:  A Preliminary Report.  Soran, OZ, Journal of Cardiac Failure 5:3 Suppl. 1 Abstract 195 1999

Enhanced External Counterpulsation in Patients With Heart Failure:  A Multicenter Feasibility Study.  Soran, O, Congestive Heart Failure 2002;8:204-208, 227.  

Improvement in Left Ventricular Performance by Enhanced External Counterpulsation in Patients With Heart Failure.  Gorcsan, J, et al.  Journal of the American College of Cardiology 2000;35(2):230A#901-5.

What Factors Predict Congestive Heart Failure During Treatment of Angina Patients with Enhanced External Counterpulsation.  Lawson, WE, et al ( and the et al. includes Dr. Roberts).  Journal of Cardiac Failure Sept. '01, Suppl. 2, Vol. 7, No. 3; Abstract 174.  

 We have established that EECP is of value in the treatment of coronary artery disease.  Chest pain decreases and the 3 to 8 year outcome data is certainly positive.  What about patients with heart failure - can EECP help them?  In China, EECP is part of the standard approach to heart failure.  A formal American study of EECP in heart failure, using a multicenter, randomized, single-blinded, controlled format, similar to the MUST-EECP study, is ongoing; preliminary studies are expected in '03.    

There are many causes of heart failure.  Heart muscle fibers can be damaged by toxins, such as excessive alcohol, or by viral invasion.  After a large heart attack, there may not be enough heart muscle left to meet the body's needs.  Longstanding hypertension or untreated valve disease can stress the heart muscle beyond its ability to compensate.  There are many causes of heart failure, but in common they all lead to impaired heart pumping function.  We measure heart pumping function as the ejection fraction - the volume of blood ejected by the heart with each beat divided by the volume of blood that fills the heart between beats.  A normal ejection fraction is 50% - the heart fills with 100 cc of blood and then ejects out 50 cc into the circulation.  A severely impaired heart may fill with 100 cc and eject out only 25 cc; here the ejection fraction is severely impaired at 25%.  We use the Functional Class 1 through 4 system to described the severity of an individual patient's symptoms, just as we do with angina.  Class I patients are fully compensated; they experience symptoms only with vigorous effort, while Class IV patients are troubled by marked fatigue and shortness of breath at rest.  The Minnesota Living with Heart Failure Questionnaire attempts to numerically quantify an individual's symptoms, with a high score being bad and a low score good; in some studies the researchers simply record how far a patient can walk in 5 minutes.  These parameters are used in the studies described below, to rate the effectiveness of EECP in the treatment of heart failure.

Heart failure occurs when the heart begins to fail as a pump.  Blood dams up behind the left heart, into the lungs, producing shortness of breath, initially with effort and then later at rest.  Ankle swelling, termed edema, occurs when blood dams up behind the right heart.  Decreased forward blood flow leads to fatigue and muscular weakness.  Blood flow to the kidneys is compromised.  Urine output falls off, and with it the kidney's ability to rid the body of wastes; toxins accumulate and the heart failure patient begins to "feel sick".  The kidney, in a desperate attempt to increase its own blood supply, releases vasoactive chemicals, such as renin, into the circulation, leading to further sodium and fluid retention,  Endothelin, a potent vasoconstrictor chemical, is elaborated, constricting blood vessels in the limbs and increasing the blood pressure.  The weakened, fluid overloaded heart can't eject blood well into the now constricted arteries, and heart failure worsens in a downward spiral.  Oxygen is incompletely utilized by the inadequately perfused muscles and internal organs, leading to free radical generation, which further damages the heart and vasculature.  Production of nitric oxide, our natural blood vessel dilator, falls off, while that of endothelin, an artery constrictor, rises.  

We know from the angina studies that EECP generates nitric oxide, a potent vasodilator, and decreases production of the vasoconstrictive angiochemicals endothelin and renin; thus the arteries dilate.  EECP lowers the systolic blood pressure, and with this the resistance against which the weakened heart must pump blood; thus forward blood flow increases.  Blood flow to the kidney increases as does kidney filtering function; edema, shortness of breath, and the sense of "sickness" should recede.  In theory, it makes sense that EECP will be helpful in heart failure.  We know from Dr. Amsterdam's article in section two that EECP is of great value in heart failure complicating a heart attack, but what will happen when outpatients with heart failure are treated with EECP?  Is EECP safe in this population?  Will they get better?  Let's look at the research available to date:   

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1.  Enhanced External Counterpulsation as Treatment for Chronic Angina in Patients with Left Ventricular Dysfunction:  A Report From the International EECP Patient Registry (IEPR).  Soran, O, et al.  CHF 2002;8:297-302         

All of our EECP patients have been entered into the  International EECP Registry, which records clinical parameters and EECP treatment outcomes.  Analysis of the registry data helps us to understand which patients benefit the most from EECP, and just as important, why.  Of the 1402 registry patients to complete a full course of EECP at the time of this study, 312, or 22%, had a severe impairment in heart pumping function, with an ejection fraction of < 35% (remember that a normal ejection fraction, or EF, is ≥ 50%).  Dr. Soran compared outcome and complication rates in these 312 patients, with poor heart function, with that of the other 1090 patients, who had normal or only mildly impaired heart pumping capacity.  Was EECP safe in these low EF patients?  Will EECP relieve their angina?                                                                                                                                                      

Baseline Status	EF < 35%	EF ≥ 35%
Duration of CADz	13 years	9 years
Prior Heart Attack	84%	62%
Prior CHF	61%	20%
Class III/IV	86%	74%

First, Soran observed that the patients with pump dysfunction were sicker to begin with (see graphic).  They had a longer history of coronary disease, more severe angina, and were three times more likely to have experienced at least one prior episode of congestive heart failure.  

 

 

In-EECP Status	EF < 35%	EF ≥ 35%
Unstable Angina	4.2%	2%
CHF	5.4%	1%
MI/Death/Revasc.	2.9%	1.7%
Death	3%	1.6%

The patients with pump dysfunction were also more difficult to treat; 79% were able to complete a full 35 course of EECP, compared to 86% of those with intact pump function.  Serious events during the 7-week program, while infrequent in both groups, occurred with greater frequency in the patients with EFs < 35%.  5% experienced an exacerbation of heart failure during their EECP program, and 4% developed unstable angina, compared to 1% CHF and 2% unstable angina rates in the patients with intact pump function.  Death during the 7-week EECP program was infrequent, 3% in the patients with pump dysfunction, and 1.6% in those with an ejection fraction above 35%.

So these patients are sicker and they are more difficult to treat.  While EECP itself is a safe procedure, patients with pump dysfunction are more likely to experience an adverse event during their 7-week treatment program, as compared to angina patients with an ejection fractios above 35%.  We don't really view this as a complication of EECP in low EF patients, but more as the natural history of the patients' underlying disease state, unfolding before we have a chance to deal with it.  While a 3% death rate sounds troubling, please realize that risks associated with bypass surgery (not possible in these patients) and medical therapy (not working in these patients) is also much greater in patients whose ejection fractions are below 35%.  With this information in mind, Dr. Soran concluded that EECP could be carried out with reasonable safety in patients with poor cardiac pumping function.  Now, will they improve?  Will the improvement stick?

Post-EECP Status	EF < 35%	EF ≥ 35%
Improved ≥ 1 Class	68%	76%
Angina/week	8.7 to 2.0	9.9 to 3.2
NTG discontinued	39%	40%
↓ in NTG use/week	6.2	7.2

The answer is:  Yes, they will improve, nearly to the degree as do patients with preserved pump function (see table).  Amongst patients who were able to complete a full 35-hour treatment course, angina improved by ≥ 1 functional class in 80% of the EF < 35% and 84% of those with preserved pump function, not a significant difference.  Now to the second question:  Will the improvement hold?

 

 

6 Months Status	EF < 35%	EF ≥ 35%
Death	9.3%	2.2%
CHF	9.9%	3.7%
Heart Attack	3.5%	3.1%
CV Hospitalization	12.3%	12.8%
Angina same/better	81%	83.8%
Angina class I/II	83.3%	72.7%
No event, gain kept	70.6%	67%

In keeping with their worse condition at baseline, 6-month event rate was greater in the low EF patients - hospitalization rate was no worse, at 12%, but CHF and death rates were, at 9.9 and 9.3% respectively, compared to rates of 3.7 and 2.2% in the patients with preserved pump function.  Again, keep in mind that we are talking about a group of patients who were felt to be too far gone for bypass surgery and in whom drug therapy alone was not working.  Now, if we look at the patients who did not have an adverse event at 6 months, we can see that the low EF patients preserved their gain nearly as well as did the angina patients with preserved pump function.

In conclusion, amongst refractory angina patients referred for EECP, those with ejection fractions below 35% are sicker to begin with, more difficult to treat, but by no means impossible to treat.  Their event rate during the 7-week treatment period is relatively increased, but by no means is it prohibitive, and remember, these are patients who in general have no other options; patient safety is thus not an issue.  Treatment outcome isn't quite as good, but these people do improve.  6 months out, 2 out of 3 remain event free, with a persistent reduction in angina.  A low ejection fraction certainly doesn't disqualify a patient from EECP.   Safety is not a limiting issue.  The following studies now look at the effectiveness of EECP in the treatment of congestive heart failure.

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2.    Efficacy and Safety of Enhanced External Counterpulsation in Mild to Moderate Heart Failure: A  Preliminary Report.  Soran, OZ, Journal of Cardiac Failure 5:3 Suppl. 1 Abstract 195, 1999.

Dr. Soran and associates used EECP to treat heart failure symptoms, not angina, in a pilot study of 6 patients.  All 6 had an ejection fraction of 35% or less and Canadian Functional Class II  symptoms - shortness of breath with moderate effort such as climbing stairs while carrying a load or walking greater than two city blocks.  One patient had to drop out after 20 treatments due to back pain; the remaining five received 35 one-hour treatments over seven weeks.  V0₂max, the amount of oxygen utilized per minute, an index of cardiac functional capacity, was measured before and after the course of EECP, along with treadmill exercise duration and Minnesota Living with Heart Failure Questionnaire score (a low score means you are doing better).  Here's what they found: 

Parameter	Pre-EECP	During EECP	% Change
Functional Class	2.0	1.2	5/6 improved
V02max	13.6	15.9	­ by 19%
Exercise Duration	592 sec.	756 sec.	­ by 34%
Minnesota Score	36	22	¯ by 35

With our understanding of the physiologic effects of EECP, we can predict that EECP will be of value in the treatment of heart failure, irrespective of one's coronary status.  Dr. Soran's study, while small, seems to corroborate our prediction and the Chinese experience (and let's face it, physicians in China are a good 20 years ahead of us here).  A large, randomized, controlled study of EECP in heart failure is in the works.  We expect that this study will confirm Dr. Soran's promising findings. 

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  3.   Enhanced External Counterpulsation in Patients With Heart Failure:  A Multicenter Feasibility Study.          Soran, O, Congestive Heart Failure 2002;8:204-208, 227.  

The PEECH study is a large, multicenter, single-blind, controlled study of EECP in the treatment of heart failure; patient enrollment is nearing completion and preliminary results are expected in '03.  To ensure that the large PEECH study of EECP in heart failure would be feasible, Dr. Soran and associates repeated their initial study of EECP in heart failure, this time with 26 patients.  19 had pump dysfunction and heart failure on the basis of one or more prior heart attacks; 7 had what is known as idiopathic heart failure (pump failure of unknown cause, or as we clinicians like to say, pump failure that the idiot pathologists cannot figure out).  All had an ejection fraction of 35% or less (average EF 23%) and Canadian Functional Class II symptoms - shortness of breath with moderate effort such as climbing stairs while carrying a load or walking greater than two city blocks.  Standard drug therapy was continued.  All were on Angiotensin Converting Enzyme Inhibitors (unless these agents could not be tolerated).  Many were on beta-blockers; 71% took Digoxin and 16% Coreg.  Edema was controlled in all (if pronounced edema is present, we will mobilize it back to the right heart during EECP, and if pumping function is impaired, then we can aggravate CHF).  So here we are looking at the effect of EECP on heart failure patients who are still experiencing symptoms despite maximal drug therapy. 

35 hours of EECP were carried out over 7 weeks; then the patients were followed over an additional 6 months.  Adverse events were recorded during the treatment and follow-up periods.  V0₂max, the amount of oxygen utilized each minute at maximal exercise, an index of cardiac functional capacity, was measured before, 1 week after, and 6 months after the course of EECP, along with treadmill exercise duration, functional class, LV power (a cardiac ultrasound measure of pumping function), and Minnesota Living with Heart Failure Questionnaire score (a low score means you are doing better).  Here’s what they found:

1^st, was EECP safe in these heart failure?  As this was a feasibility study, the focus was on safety; oxygen saturation and the patient’s clinical condition were closely monitored over the 844 treatment-hours provided.  46 adverse events were reported in 23 patients; 22 occurred during the 7-week treatment period, and 24 over the 6-month follow-up period.  Of the 46 events, only 14 were classified as serious (led to hospitalization); 1 occurred during the pre-EECP baseline period, 3 during the 7-week EECP program, and 10 during the 6-month follow-up period.  None of the serious adverse events were felt to be treatment-related; rather they were felt to be related to the patient’s underlying cardiomyopathy process.  Of the 22 adverse events that occurred during the 7-week treatment period, 10 occurred during EECP treatment.  Three patients dropped out before 7 weeks; one due to back pain, one due to a flare-up of arrhythmia, and one due to progressive heart failure.  23 of the original 26 patients completed the planned 7 weeks of EECP therapy, and 18 participated in the 6-month follow-up testing.  As adverse events are anticipated in this type of patient, with CHF and severely impaired systolic function, the investigators concluded that EECP can be administered safely in patients with medically addressed CHF, and that properly administered EECP does not aggravate CHF.

 

OK, so EECP is safe in heart failure patients, but will EECP help?  First, let’s look at exercise capacity, as measured by the patients' treadmill time and peak oxygen uptake values.  Treadmill time increased by 21%, or just over one minute, following EECP; the effect was fairly well maintained, remaining 16% above baseline at 6 months.  

 

     

 

 

Peak oxygen uptake, perhaps a better indicator of cardiovascular fitness, increased by 7% with EECP, and improved further to 27% above baseline at the 6 month point.  Patients with non-coronary (idiopathic) heart failure did just as well with EECP as did those with CHF due to prior heart attack.  Thus EECP is helping with heart failure per se; it is not simply improving blood flow to blocked arteries.  

 

Quality of life improved following EECP; here again there was no real difference in outcome between the  prior heart attack and idiopathic heart failure patients.  For the group, the improvement was reasonably well  maintained at six months; the coronary (ischemic) patients even improved a little more over this interval.   

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4.  Improvement in Left Ventricular Performance by Enhanced External Counterpulsation in Patients With Heart Failure.  Gorcsan, J, et al.  Journal of the American College of Cardiology 2000;35(2):230A#901-5.