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American Government has Launched a 30 million worth of scientific Clinical trial to assess Chelation therapy.

http://nccam.nih.gov/news/2002/chelation/pressrelease.htm





NIH Launches Large Clinical Trial on EDTA Chelation Therapy for Coronary Artery Disease


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NIH News Release
National Institutes of Health
National Center for Complementary and Alternative Medicine (NCCAM)
National Heart, Lung, and Blood Institute


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For immediate release:
Wednesday, August 7, 2002
Contact:
NCCAM Communications Office, 301-451-8876
NHLBI Communications Office, 301-496-4236


The National Center for Complementary and Alternative Medicine (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI), components of the National Institutes of Health (NIH), have launched the first large-scale clinical trial to determine the safety and efficacy of EDTA chelation therapy in individuals with coronary artery disease, the leading cause of death for both men and women in the United States.

The 5-year Trial To Assess Chelation Therapy (TACT) will involve over 2,300 patients at more than 100 research sites across the country.

"The public health imperative to undertake a definitive study of chelation therapy is clear. The widespread use of chelation therapy in lieu of established therapies, the lack of adequate prior research to verify its safety and effectiveness, and the overall impact of coronary artery disease convinced NIH that the time is right to launch this rigorous study," said Stephen E. Straus, M.D., NCCAM Director.

Over 800,000 patient visits were made for chelation therapy in the United States in 1997. Chelation therapy involves the use of EDTA (ethylene diamine tetra-acetic acid), a synthetic amino acid that is administered intravenously (through the veins). EDTA, which effectively speeds removal of heavy metals and minerals such as lead, iron, copper, and calcium from the blood, is approved by the U.S. Food and Drug Administration (FDA) for use in treating lead poisoning and toxicity from other heavy metals. Although it is not approved by the FDA to treat coronary artery disease, some physicians and alternative medicine practitioners have recommended EDTA chelation as a way to treat this disorder.

Coronary artery disease (CAD) is a type of heart disease in which the coronary arteries (vessels that supply oxygen-carrying blood to the heart) become blocked by deposits of a fatty substance called plaque. As plaque builds, the arteries become narrower and less oxygen and nutrients are transported to the heart for proper function. CAD can lead to serious health problems such as angina (pain caused by insufficient oxygen-carrying blood reaching the heart) and heart attack.

There are standard and well-proven ways to reduce the risks or complications of CAD. These include stopping smoking and controlling high blood pressure and high blood cholesterol through lifestyle changes and medication. More invasive procedures are used to treat symptomatic CAD including balloon angioplasty (dilation of a blocked artery to open it up) or coronary artery bypass surgery (using arteries or veins from other areas of the body to create detours for blood flow around areas of blockage in the heart artery).

"NCCAM's leadership in initiating and supporting this study is to be commended," said NHLBI Director Claude Lenfant, M.D. "It is important for heart disease patients to know whether we should add chelation therapy to the list of proven treatments for coronary artery disease. Scientific evidence is needed to resolve this issue. And only a large clinical trial can definitively answer the question of whether chelation treatment is truly safe and effective," added Lenfant.

The randomized, double-blind study will enroll 2,372 patients aged 50 or older who have had a heart attack. The $30 million study, led by Gervasio A. Lamas, M.D., director of cardiovascular research and academic affairs at Mount Sinai Medical Center-Miami Heart Institute in Miami Beach, Florida, will test whether EDTA chelation therapy and/or high-dose vitamin therapy is effective for the treatment of CAD. Vitamin and mineral supplements, consistent with the regimen used by practitioners who deliver EDTA chelation therapy, will be used in the study.

Following baseline assessments, about 1,186 patients will be randomly assigned to receive a standardized chelation solution, and about 1,186 patients will receive a placebo (dummy) solution. Each of these two groups will additionally be randomized to receive high-dose vitamin/mineral supplements versus low-dose vitamin/mineral supplements. Study participants will receive 30 weekly infusions of EDTA chelation therapy followed by 10 bimonthly infusions. All patients enrolled will be followed until the end of the study to observe any significant clinical benefits or side effects. The primary study endpoint (a marker of improvement) of this trial will be a composite of heart attack, stroke, hospitalization for angina (pain associated with CAD), coronary revascularization, and death. The study will also evaluate cardiac deaths, nonfatal heart attacks, health-related quality of life, and cost effectiveness, among other factors.

TACT includes a Data Coordinating Center led by Kerry Lee, Ph.D., and a Quality of Life Coordinating Center led by Daniel Mark, M.D., M.P.H., both at the Duke Clinical Research Institute in Durham, North Carolina. In addition, an independent Data Safety Monitoring Board will oversee the study.

Patient recruitment for the study is expected to begin in March 2003, after preparations are completed to enroll participants at the many study sites.

Questions and answers about this study are located at www.nccam.nih.gov/news/2002/chelation/q-and-a.htm.

Information about the study, locations, and enrollment will be available from the NCCAM Web site and from ClinicalTrials.gov, the NIH Web site for clinical trial information.


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The National Center for Complementary and Alternative Medicine (NCCAM) is dedicated to exploring complementary and alternative medical (CAM) practices in the context of rigorous science, training CAM researchers, and disseminating authoritative information to the public and professionals. For additional information, call NCCAM's Clearinghouse toll free at 1-888-644-6226, or visit the NCCAM Web site at nccam.nih.gov.

The National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. For additional information, contact the NHLBI Health Information Center at 301-592-8573, or visit the NHLBI Web site at www.nhlbi.nih.gov.



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Hyperthermia in Cancer Treatment. National Cancer Institute

Hyperthermia in Cancer Treatment. National Cancer Institute
Posted 02 Jul 2011 in Hyperthermia.
Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures (up to 113°F) to damage and kill cancer cells (see Question 1).
Hyperthermia is almost always used with other forms of cancer therapy, such as radiation therapy and chemotherapy (see Question 2).
Several methods of hyperthermia are currently under study, including local, regional, and whole-body hyperthermia (see Question 3).
Many clinical trials (research studies) are being conducted to evaluate the effectiveness of hyperthermia (see Question 5).
1. What is hyperthermia? Hyperthermia (also called thermal therapy or thermotherapy) is a type of cancer treatment in which body tissue is exposed to high temperatures (up to 113°F). Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues (1). By killing cancer cells and damaging proteins and structures within cells (2), hyperthermia may shrink tumors.
Hyperthermia is under study in clinical trials (research studies with people) and is not widely available (see Question 5).
2. How is hyperthermia used to treat cancer?Hyperthermia is almost always used with other forms of cancer therapy, such as radiation therapy and chemotherapy (1, 3). Hyperthermia may make some cancer cells more sensitive to radiation or harm other cancer cells that radiation cannot damage. When hyperthermia and radiation therapy are combined, they are often given within an hour of each other. Hyperthermia can also enhance the effects of certain anticancer drugs.
Numerous clinical trials have studied hyperthermia in combination with radiation therapy and/or chemotherapy. These studies have focused on the treatment of many types of cancer, including sarcoma, melanoma, and cancers of the head and neck, brain, lung, esophagus, breast, bladder, rectum, liver, appendix, cervix, and peritoneal lining (mesothelioma) (1, 3, 4, 5, 6, 7). Many of these studies, but not all, have shown a significant reduction in tumor size when hyperthermia is combined with other treatments (1, 3, 6, 7). However, not all of these studies have shown increased survival in patients receiving the combined treatments (3, 5, 7).
3. What are the different methods of hyperthermia? Several methods of hyperthermia are currently under study, including local, regional, and whole-body hyperthermia (1, 3, 4, 5, 6, 7, 8, 9).
In local hyperthermia, heat is applied to a small area, such as a tumor, using various techniques that deliver energy to heat the tumor. Different types of energy may be used to apply heat, including microwave, radiofrequency, and ultrasound. Depending on the tumor location, there are several approaches to local hyperthermia:
External approaches are used to treat tumors that are in or just below the skin. External applicators are positioned around or near the appropriate region, and energy is focused on the tumor to raise its temperature.
Intraluminal or endocavitary methods may be used to treat tumors within or near body cavities, such as the esophagus or rectum. Probes are placed inside the cavity and inserted into the tumor to deliver energy and heat the area directly.
Interstitial techniques are used to treat tumors deep within the body, such as brain tumors. This technique allows the tumor to be heated to higher temperatures than external techniques. Under anesthesia, probes or needles are inserted into the tumor. Imaging techniques, such as ultrasound, may be used to make sure the probe is properly positioned within the tumor. The heat source is then inserted into the probe. Radiofrequency ablation (RFA) is a type of interstitial hyperthermia that uses radio waves to heat and kill cancer cells.
In regional hyperthermia, various approaches may be used to heat large areas of tissue, such as a body cavity, organ, or limb.
Deep tissue approaches may be used to treat cancers within the body, such as cervical or bladder cancer. External applicators are positioned around the body cavity or organ to be treated, and microwave or radiofrequency energy is focused on the area to raise its temperature.
Regional perfusion techniques can be used to treat cancers in the arms and legs, such as melanoma, or cancer in some organs, such as the liver or lung. In this procedure, some of the patient’s blood is removed, heated, and then pumped (perfused) back into the limb or organ. Anticancer drugs are commonly given during this treatment.
Continuous hyperthermic peritoneal perfusion (CHPP) is a technique used to treat cancers within the peritoneal cavity (the space within the abdomen that contains the intestines, stomach, and liver), including primary peritoneal mesothelioma and stomach cancer. During surgery, heated anticancer drugs flow from a warming device through the peritoneal cavity. The peritoneal cavity temperature reaches 106–108°F.
Whole-body hyperthermia is used to treat metastatic cancer that has spread throughout the body. This can be accomplished by several techniques that raise the body temperature to 107–108°F, including the use of thermal chambers (similar to large incubators) or hot water blankets.
The effectiveness of hyperthermia treatment is related to the temperature achieved during the treatment, as well as the length of treatment and cell and tissue characteristics (1, 2). To ensure that the desired temperature is reached, but not exceeded, the temperature of the tumor and surrounding tissue is monitored throughout hyperthermia treatment (3, 5, 7). Using local anesthesia, the doctor inserts small needles or tubes with tiny thermometers into the treatment area to monitor the temperature. Imaging techniques, such as CT (computed tomography), may be used to make sure the probes are properly positioned (5).
4. Does hyperthermia have any complications or side effects?Most normal tissues are not damaged during hyperthermia if the temperature remains under 111°F. However, due to regional differences in tissue characteristics, higher temperatures may occur in various spots. This can result in burns, blisters, discomfort, or pain (1, 5, 7). Perfusion techniques can cause tissue swelling, blood clots, bleeding, and other damage to the normal tissues in the perfused area; however, most of these side effects are temporary. Whole-body hyperthermia can cause more serious side effects, including cardiac and vascular disorders, but these effects are uncommon (1, 3, 7). Diarrhea, nausea, and vomiting are commonly observed after whole-body hyperthermia (7).
5. What does the future hold for hyperthermia? A number of challenges must be overcome before hyperthermia can be considered a standard treatment for cancer (1, 3, 6, 7). Many clinical trials are being conducted to evaluate the effectiveness of hyperthermia. Some trials continue to research hyperthermia in combination with other therapies for the treatment of different cancers. Other studies focus on improving hyperthermia techniques.
To learn more about clinical trials, call the National Cancer Institute’s (NCI) Cancer Information Service at the telephone number listed below or visit NCI’s Clinical Trials Home Page.

Selected References:
van der Zee J. Heating the patient: A promising approach? Annals of Oncology 2002; 13:1173–1184.
Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Critical Reviews in Oncology/Hematology 2002; 43:33–56.
Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in combined treatment of cancer. The Lancet Oncology 2002; 3:487–497.
Alexander HR. Isolation perfusion. In: DeVita VT Jr., Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. Vol. 1 and 2. 6th ed. Philadelphia: Lippincott Williams and Wilkins, 2001.
Falk MH, Issels RD. Hyperthermia in oncology. International Journal of Hyperthermia 2001; 17(1):1–18.
Dewhirst MW, Gibbs FA Jr, Roemer RB, Samulski TV. Hyperthermia. In: Gunderson LL, Tepper JE, editors. Clinical Radiation Oncology. 1st ed. New York, NY: Churchill Livingstone, 2000.
Kapp DS, Hahn GM, Carlson RW. Principles of Hyperthermia. In: Bast RC Jr., Kufe DW, Pollock RE, et al., editors. Cancer Medicine e.5. 5th ed. Hamilton, Ontario: B.C. Decker Inc., 2000.
Feldman AL, Libutti SK, Pingpank JF, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. Journal of Clinical Oncology 2003; 21(24):4560–4567.
Chang E, Alexander HR, Libutti SK, et al. Laparoscopic continuous hyperthermic peritoneal perfusion. Journal of the American College of Surgeons 2001; 193(2):225–229.

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Posted 02 Jul 2011 in Hyperthermia
by James Street
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Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia

Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia
Li Sun,1,5 Wei Zhou,1,5 Christian Mueller,1 Clemens Sommer,2 Sabine Heiland,3 Alexander T Bauer,4 Hugo H Marti,4 and Roland Veltkamp1,*
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Abstract

Hyperbaric oxygen (HBO) and normobaric hyperoxia (NBO) protect the brain parenchyma and the cerebral microcirculation against ischemia. We studied their effect on secondary hemorrhage after thrombolysis in two thromboembolic middle cerebral artery occlusion (MCAO) (tMCAO) models. Beginning 60 minutes after tMCAO with either thrombin-induced thromboemboli (TT) or calcium-induced thromboemboli (CT), spontaneously hypertensive rats (n=96) breathed either air, 100% O2 (NBO), or 100% O2 at 3 bar (HBO) for 1 hour. Immediately thereafter, recombinant tissue plasminogen activator (rt-PA, 9 mg/kg) was injected. Although significant reperfusion was observed after thrombolysis in TT-tMCAO, vascular occlusion persisted in CT-tMCAO. In TT-tMCAO, NBO and HBO significantly reduced diffusion-weighted imaging–magnetic resonance imaging (MRI) lesion volume and postischemic blood–brain barrier (BBB) permeability on postcontrast T1-weighted images. NBO and, significantly more potently, HBO reduced macroscopic hemorrhage on T2* MRI and on corresponding postmortem cryosections. Oxygen therapy lowered hemoglobin content and attenuated activation of matrix metalloproteinases in the ischemic hemisphere. In contrast, NBO and HBO failed to reduce infarct size in CT but both decreased BBB damage and microscopic hemorrhagic transformation. Only HBO reduced hemoglobin extravasation in the ischemic hemisphere. In conclusion, NBO and HBO decrease infarct size after thromboembolic ischemia only if recanalization is successful. As NBO and HBO also reduce postthrombolytic intracerebral hemorrhage, combining the two with thrombolysis seems promising.
Keywords: cerebral ischemia, hemorrhage, hyperbaric oxygen, normobaric hyperoxia, thrombolysis
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Introduction

Secondary hemorrhage is a feared complication of thrombolysis in ischemic stroke. In large clinical trials, thrombolysis has been shown to increase the risk of symptomatic intracerebral hemorrhage about sixfold and the mortality associated with symptomatic hemorrhage about 10-fold (Hacke et al, 2004). Accordingly, preventing secondary hemorrhage after thrombolysis has become an important goal of ischemic stroke therapy. In preclinical and clinical studies, ischemic blood–brain barrier (BBB) damage is associated with secondary hemorrhage after thrombolysis (Del Zoppo et al, 1998; Kahles et al, 2005; Kastrup et al, 2008; Wang et al, 2003). Mediators of BBB damage include free radical-induced reperfusion injury, various cytokines, and proteases. The activation and proteolytic activity of matrix metalloproteinases (MMPs), particularly MMP-9, are key factors in the proteolytic disruption of the basal lamina and tight junctions of the BBB (Hawkins and Davis, 2005; Wang et al, 2003).

Oxygen therapy has offered a simple, but plausible therapeutic approach in experimental cerebral ischemia for many years and was shown to be particularly effective when therapy was started early in reperfusion models (Calvert et al, 2007; Helms et al, 2005; Nighoghossian and Trouillas, 1997; Singhal, 2007; Poli and Veltkamp, 2009; Veltkamp et al, 2000; Zhang et al, 2005). Beyond protection of the brain parenchyma, oxygen therapy may also have beneficial effects on the postischemic microcirculation. In previous studies, hyperbaric oxygen (HBO) and normobaric hyperoxia (NBO) attenuated BBB permeability after focal and global ischemia (Mink and Dutka, 1995; Singhal et al, 2002; Veltkamp et al, 2005a). However, the effects of NBO and HBO on hemorrhagic transformation after focal cerebral ischemia are controversial (Liu et al, 2009; Qin et al, 2007; Henninger et al, 2006, 2009). Furthermore, the effects of these two forms of oxygen therapy on secondary hemorrhage and the underlying BBB damage after experimental thrombolysis have not been directly compared to date.

The purpose of this study was to examine the differences in the effectiveness of HBO and NBO in combination with intravenous thrombolysis after thromboembolic middle cerebral artery occlusion (tMCAO). Specifically, we tested the impact of oxygen therapy on postischemic BBB damage and secondary hemorrhage in two thromboembolic stroke models in which thrombolysis recanalizes or fails to reopen the MCA, respectively.
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Materials and methods

All experiments were performed on spontaneously hypertensive male rats weighing 300 to 350 g (Janvier, Le Genest St Isle, France). The study and all associated procedures were approved by the governmental animal care authorities (Regierungspraesidium, Karlsruhe, Germany). Using a face mask, anesthesia was induced with 4% halothane in O2 and continued with 0.8% to 1.2% halothane in a 70/30 mixture of nitrous oxide/oxygen under spontaneous respiration. During surgery, rectal temperature was maintained at 37°C with a thermostatically controlled heating pad. The femoral artery and vein were cannulated with PE-50 polyethylene tubing for continuous monitoring of arterial blood pressure and heart rate, to provide samples for blood gas measurements, and to inject the magnetic resonance contrast agent.
Thrombus Generation

Focal cerebral ischemia was induced using the tMCAO model described by Toomey et al (2002) with some modifications. Thrombi were generated in two different ways: for thrombin-induced thromboemboli (TT), 500 μL of fresh arterial blood from a donor rat were drawn into an Eppendorf tube and mixed with 1.0 National Institutes of Health (NIH) units of human thrombin (Sigma Aldrich, St Louis, MO, USA) and 5 μL of 1 mol/L CaCl2 for a final CaCl2 concentration of 10 mmol/L. Within 5 seconds, a small portion of the mixture was drawn into a 15-cm-long PE-50 tube and allowed to coagulate for 2 hours at 37°C. Then, the clot was transferred from the tube into a Petri dish, which was then filled with saline and stored at 4°C for 12 hours. Before MCAO, the clot was incubated in deionized water at room temperature for 5 minutes. Subsequently, the clot was placed into isotonic saline and inspected under a microscope at fivefold magnification. Twelve thrombi—each 0.35 mm in diameter and 1.5 mm in length—were cut under the microscope and then drawn into PE-50 tubing.

For the calcium-rich thromboemboli (CT), whole arterial blood from a donor rat was drawn into a PE-50 tube where it was allowed to coagulate spontaneously for 2 hours at 37°C. Then, the clot was transferred from the tube into a dish where it was exposed to a 20 mmol/L calcium solution for 1 minute. After transfer into saline solution, the clot was dissected as described for the TT.
Surgical Procedure and Experimental Protocol

The right external carotid artery was permanently ligated distally and mobilized as described (Toomey et al, 2002). The PE-50 catheter with 12 clots was inserted into the right external carotid artery proximal to the ligation and advanced through the bifurcation into the proximal internal carotid artery. Ischemia was induced by injecting the 12 clots into the internal carotid artery over a 30-seconds period with 50 μL of saline. After removing the catheter, ligating the proximal external carotid artery and closing the neck, rats were placed into a magnetic resonance imaging (MRI) scanner (Bruker Biospec, 2.35 T, Karlsruhe, Germany).

Perfusion-weighted imaging (PWI) was performed to ensure hypoperfusion in the territory of the occluded MCA in all animals. After PWI, rats were allowed to wake up. Sixty minutes after injecting the thrombus, animals were randomly assigned to one of three groups. Animals breathed either air, 100% O2 at ambient pressure (NBO), or 100% O2 at 3 bar (HBO) for 60 minutes in a pressure chamber. Immediately after oxygen therapy, animals received recombinant tissue plasminogen activator (rt-PA) intravenously (9 mg/kg in 2 mL H2O; Actilyse, Boehringer Ingelheim, Ingelheim am Rhein, Germany). Ten percent of the solution was injected as a bolus; the remainder was infused over a 30-minutes period through the femoral vein. In all groups, a PWI–MRI was performed after the end of the rt-PA infusion (i.e., 2.5 hours after tMCAO) and 24 hours after tMCAO to document the perfusion status after thrombolysis and at the end of the experiment.
Magnetic Resonance Imaging Protocol

For PWI, we used a gradient-echo–echo-planar imaging sequence (repetition time (TR)=1 second, echo time (TE)=15 milliseconds, field of view=4.5 cm × 4.5 cm, 4 slices, thickness=2 mm, 20 repetitions with a time resolution of 1 second/image data set) to monitor the bolus passage of 1 mmol/kg of a paramagnetic contrast agent (Omniscan, Nycomed Amersham, Oslo, Norway). For diffusion-weighted MRI, we acquired a spin-echo–echo-planar imaging sequence (b value=200, 300, 400, 500, 600, and 700 seconds/mm2) 2.5 and 24 hours after tMCAO. The MR protocol also comprised a T1 spin-echo sequence with a TR of 400 milliseconds, TE of 15 milliseconds, a flip angle of 90°, a matrix of 128 × 128, field of view=4 cm × 4 cm, and 6 slices with slice thickness=2 mm; the number of averages was 8. T1-weighted imaging was performed 10 minutes after injecting the contrast agent and again 2.5 and 24 hours after embolization. T2*-weighted imaging was performed 24 hours after embolization with a fast low angle shot sequence (TR=300 milliseconds, TE=20 milliseconds, flip angle=20°C, matrix 128 × 96, field of view=4 cm × 4 cm, number of slices=6, and number of averages=4).
Magnetic Resonance Imaging Data Analysis

For analysis of PWI, the relative cerebral blood volume (rCBV) and the relative mean transit time were calculated in two predefined corresponding regions of interest in the parietal cortex of both hemispheres from the signal–time curve determined from the PWI data set as described earlier (Heiland et al, 1997). Diffusion-weighted imaging (DWI) and T1w data were analyzed by encircling areas of abnormal signal intensity for each MR section using a side-to-side comparison on the screen. Volume of abnormally hyperintense signals on DWI and postcontrast enhancement on T1w was calculated by multiplying the total area with a 2-μm section thickness. Areas of abnormally hypointense signal on T2* reflecting macroscopic hemorrhage were measured by a blinded rater. To validate that the DWI lesion size corresponded to parenchymal histologic damage, we analyzed the infarct area on histologic sections at the level of the bregma 24 hours after tMCAO in a subgroup of animals.
Macroscopic Examination of Secondary Hemorrhage

Twenty-four hours after TT-MCAO, brains (n=10/group) were removed. Unstained coronal cryosections were photographed without magnification. Macroscopic evidence of intracerebral hemorrhage was compared with T2* on corresponding sections.
Spectrophotometric Hemoglobin Assay

The hemoglobin content of brains was quantified with a spectrophotometric assay as described earlier with some modifications (Choudhri et al, 1997). Twenty-four hours after MCAO, rats were deeply anesthetized and transcardially perfused with 100 mL of saline. Brains were rapidly removed, divided into left and right hemisphere, frozen in isopentane, and stored at −80°C. The brain hemispheres were homogenized in 1.0 mL of PBS on ice for 30 seconds, insonated with pulse ultrasound for 1 minute, and centrifuged at 13,000 r.p.m. for 30 minutes. After the hemoglobin-containing supernatant was collected, 120 μL of Drabkin's reagent (Sigma Diagnostics, St Louis, MO, USA; K3Fe(CN)6 200 mg/L, KCN 50 mg/L, NaHCO3 1 g/L, pH 8.6) was added to a 30-μL aliquot and the mixture was allowed to stand for 15 minutes. The optical density was then measured at a wavelength of 540 nm with a spectrophotometer (Synergy 2 Multi-Detection Microplate Reader, BioTec, St Louis, MO, USA). To verify that the measured absorbance after these procedures reflected the amount of hemoglobin, blood was obtained from naive mice by cardiac puncture after anesthesia. Incremental aliquots of this blood (4, 8, 16, 20, 32, and 50 μL) were added to freshly homogenized brain tissue obtained from untreated mice to generate a standard absorbance curve. This curve showed a linear relationship between added blood volume and optical density (Supplementary Figure 1).
Histologic Assessment of Hemorrhagic Transformation

In animals without macroscopically visible hemorrhage on T2*, histologic staining was performed using trichrome. Twenty-four hours after CT-tMCAO, rats were deeply anesthetized and transcardially perfused with 100 mL of saline and fixed with 100 mL 4% paraformaldehyde (PFA). Brains were rapidly removed and postfixed in 1% PFA at 4°C. After embedding in paraffin, 5-μm coronal sections were deparaffinized, hydrated, and treated with Harris hemalaun solution for 5 minutes. Then, sections were incubated with a trichrome solution (pH 3.4, 1.2% chromotrop 2R, 1.2% wolframatophosphoracid, 0.6% fast green FCF, and 1% acetic acid). After rinsing briefly, sections were dehydrated, mounted, coverslipped, and observed under a microscope (Leica, Wetzlar, Germany). To assess the severity of erythrocytic extravasations, a blinded rater used a predefined semiquantitative scale (score 0 to 5, with lower scores representing fewer intraparenchymal erythrocytes, Supplementary Figure 2).
Gelatin Zymography

Corresponding samples of ischemic and nonischemic hemispheres were taken from a series of 20-μm-thick coronal cryosections with 1.2 mm distance and homogenized in ice-cold lysis buffer (50 mmol/L Tris–HCl, pH 7.5, 150 mmol/L NaCl, 5 mmol/L CaCl2, 0.05% Brij-35, 0.02% NaN3, and 1% Triton X-100). After centrifugation, the supernatant was collected and protein concentration of each sample was determined in triplicate using Bradford reagent (Bio-Rad Laboratories GmbH, Munich, Germany). Aliquots of lysates containing 50 μg protein were subjected to electrophoresis on 10% sodium dodecyl sulfate polyacrylamide gel copolymerized with 1 mg/ml gelatin (Sigma Aldrich, Munich, Germany) under nonreducing conditions. After washing in 2.5% Triton-X 100 for 2 hours, gels were incubated in a developing buffer containing 50 mmol/L Tris–HCl, pH 7.5, 150 mmol/L NaCl, 5 mmol/L CaCl2, 0.02% Brij-35, and 0.02% NaN3 for 60 hours. Gels were then stained with 0.125% Coomassie blue R-250 in 10% acetic acid and 50% methanol for 30 minutes before they were destained in a solution containing 5% acetic acid and 25% methanol until clear bands appeared on a dark blue background. After scanning (MCID 7.0, InterFocus GmbH, Mering, Germany) densitometry of bands was performed using the public domain Image J software (National Institutes of Health, Bethesda, MD, USA). A mixture of human MMP-9 and MMP-2 (Chemicon International, Millipore, Schwalbach, Germany) was used as positive control.
Statistical Analysis

All values are expressed as mean±standard deviation. For comparison of physiologic values, infarct volumes, and MRI data, analysis of variance (ANOVA) was used, followed by post hoc Fisher's protected least significant difference test. The scores on the histologic hemorrhage scale were assessed by the Kruskal–Wallis test and then by the Mann–Whitney U-test. All analyses were performed using SPSS analysis software. A P-value <0.05 was considered statistically significant.Go to:Results
Physiologic parameters before tMCAO and 5 minutes after reperfusion did not differ significantly among groups except for arterial pO2 (Table 1). Arterial pO2 in the HBO group could only be measured after opening the pressure chamber.Table 1
Table 1Physiologic parameters
On injecting emboli PWI, signal intensity declined in the ischemic hemisphere. The rCBV (ischemic and nonischemic hemisphere) did not differ among groups 20 minutes after tMCAO (P>0.5, ANOVA). Thus, ischemia was equally severe in all groups initially. In TT-tMCAO, thrombolysis improved rCBV in cortex at 2.5 and 24 hours after MCAO in all three groups (P<0.05, ANOVA). Relative CBV changes did not differ between 2.5 and 24 hours after embolism (P>0.5). In contrast, in CT-tMCAO, PWI changes did not reverse after rt-PA infusion (i.e., 2.5 hours after MCAO) and 24 hours after MCAO. No significant differences in rCBV were observed at any time point after CT-tMCAO among all groups (P>0.5, ANOVA). Thus, rt-PA did not induce recanalization in CT-tMCAO (Supplementary Figure 3).
Oxygen Therapies Reduce Ischemic Lesion in Recanalized but not in Permanent Thrombembolic Middle Cerebral Artery Occlusion

To delineate the brain parenchymal damage, lesion volume was measured on DWI–MRI. Hyperintensity on DWI correlated well with infarct volume on histologic sections (r=0.76, P=0.001), which was similar to the results of an earlier study (Veltkamp et al, 2005a). An abnormally hyperintense signal on DWI was detected already 2.5 hours after MCAO and became more extensive 24 hours after MCAO. In TT-tMCAO, NBO and HBO significantly reduced lesion volume on DWI compared with air (Figure 1). In contrast, in CT-tMCAO, only a transient trend toward reduced lesion volume was detected on DWI–MRI in the HBO group at 2.5 hours but no differences were seen at 24 hours after tMCAO (Figure 1). Hence, oxygen therapy did not reduce lesion volume in permanent tMCAO.
Figure 1
Figure 1
Hyperintense lesion volumes on magnetic resonance diffusion-weighted images at 2.5 and 24 hours after thromboembolic middle cerebral artery occlusion (tMCAO) (mm3). (A) In thrombin-induced thromboemboli-tMCAO, lesion volume on diffusion-weighted imaging ...
Normobaric Hyperoxia and Hyperbaric Oxygen Reduce Blood–Brain Barrier Damage

Postischemic microvascular permeability was analyzed on postcontrast T1w images, which correlates well with Evans blue extravasation (data not shown). An abnormally hyperintense signal on postcontrast T1w images was detected 2.5 hours after injecting emboli. In TT-tMCAO, volumes of enhancement on T1w images at this time point were 105.8±21.6 mm3 in the air, 89.5±22.2 mm3 in the NBO, and 48.7±10.9 mm3 in the HBO group (P<0.001, n=12 per group). At 24 hours after tMCAO, volumes of enhancement on T1w images were 129.1±20.2 mm3 in air-, 89.5±22.8 mm3 in NBO-, and 51.3±11.4 mm3 in HBO-treated rats. (Figure 2) Thus, NBO and, more effectively, HBO significantly reduced postischemic BBB damage on T1w images 24 hours after tMCAO with reperfusion (P<0.001, ANOVA). In CT-tMCAO, HBO also significantly reduced postischemic, enhancing T1 volumes 24 hours after tMCAO (P<0.05, ANOVA) whereas NBO failed to attenuate the enhancing volume on T1w images (P=0.18, ANOVA) (Figure 2).Figure 2
Figure 2Volume of enhancement on postcontrast T1w magnetic resonance images 2.5 and 24 hours after thromboembolic middle cerebral artery occlusion (tMCAO) (mm3). (A) In thrombin-induced thromboemboli-tMCAO, normobaric hyperoxia (NBO) and, more effectively, hyperbaric ...Macroscopic Evidence of Secondary Hemorrhage
T2* MR imaging was used to detect ‘macroscopic' intracerebral hemorrhage because it corresponded well to hemorrhage on unstained coronal cryosections (Figures 3B and 3C). An abnormally hypointense signal reflecting hemorrhage was observed on T2* MR images 24 hours after embolization (Figure 3). In TT-tMCAO with recanalization, the hypointense T2* signal was found in all animals except for 2 of the 11 HBO-treated rats. (Figures 3B and 3C) The mean number of MRI sections with hypointense T2* signal was 3.8±1.0 in air-, 2.4±1.2 in NBO-, and 1.3±0.9 in HBO-treated rats. Thus, both NBO and HBO induced a significant reduction in macroscopic hemorrhage on T2* MR images (P< 0.01, Kruskal–Wallis test, Mann–Whitney U-test, n=11/group). Moreover, macroscopic hemorrhage was significantly smaller in HBO- than in NBO-treated mice (P=0.037, Mann–Whitney U-test, n=11/group) (Figure 3). Interestingly, the area of hypointense T2* signal at 24 hours after MCAO was located within the area of intense postcontrast enhancement on T1w images at 2.5 hours after MACO (Figure 3). In addition, enhancing T1w lesion at 2.5 hours after MCAO correlated well with the hypointense T2* signal at 24 hours after MACO (r=0.919, P<0.001, Spearman). Thus, a circumscribed, early increase in BBB permeability appeared to indicate a risk for later secondary hemorrhage. Moreover, hypointense T2* signals were mainly observed within areas of the ischemic parenchymal DWI lesion in all the three groups (Figure 4).Figure 3
Figure 3Correspondence of blood–brain barrier damage, infarct lesion, and secondary hemorrhage. (A) Postcontrast enhancement on T1w postcontrast magnetic resonance image (arrow). (B) Corresponding T2* magnetic resonance image showing ‘macroscopic' ...Figure 4
Figure 4Multimodal magnetic resonance imaging images showing the topography of the parenchymal infarct (diffusion-weighted imaging (DWI) at 24 hours), blood–brain barrier permeability (postcontrast T1w at 2.5 hours), and hemorrhage (T2* at 24 ...In permanent CT-tMCAO, only 3/10 animals in the air group and none of the NBO- or HBO-treated rats showed such ‘macroscopic' hemorrhage on T2* MRI, despite thrombolysis.Oxygen Therapy Reduces Postischemic Hemoglobin Extravasation
To quantify hemorrhagic transformation, total brain hemoglobin contents were analyzed 24 hours after embolization using a spectrophotometric assay. On the basis of the standard absorbance curve, the measured absorption of optical density was converted to hemoglobin volume. A pronounced increase in hemoglobin content in the ischemic hemisphere was observed as compared with the contralateral hemisphere in the air-treated rats. In groups with recanalized MCA, both NBO (14.2±5.9 μL) and HBO (11.2±5.7 μL) significantly decreased the mean hemoglobin volume as compared with air in the ischemic hemisphere (25.4±5.6 μL, P<0.05, n=5 per group, ANOVA). Again, there was less hemorrhagic transformation in permanent than in recanalized tMCAO. In CT-tMCAO, only HBO (4.9±2.2 μL) reduced hemoglobin volume as compared with air (12.8±8.3 μL, P<0.05, n=10, ANOVA). No significant differences in mean hemoglobin contents were found between NBO (8.3±4.1 μL) and air (12.8±8.3 μL, P=0.32) or between NBO and HBO (P=0.79) (Figure 5).Figure 5
Figure 5Hemoglobin spectrophotometry of perfused ischemic brain hemisphere and expression of matrix metalloproteinase (MMP)-2 and MMP-9 24 hours after thromboembolic middle cerebral artery occlusion (tMCAO). (A) In thrombin-induced thromboemboli (TT)-MCAO, both ...Normobaric Hyperoxia and Hyperbaric Oxygen Attenuate Erythrocytic Extravasation
As ‘macroscopic' hemorrhage was rarely found after CT-tMCAO, the extent of hemorrhagic transformation was also quantified on trichrome sections at the level of the bregma +0.26 mm (commissura anterior) using a predefined semiquantitative scale. No erythrocytic extravasation was found in the contralateral hemisphere (Figure 6). In contrast, a leakage of erythrocytes into brain tissue was observed in cortex and subcortex throughout the ischemic tissue (Figure 6). However, dense accumulation of erythrocytes developed predominantly in the striatum and in the ventral cortex (Figure 6). Mean scores of erythrocytic extravasation were 4.1±1.3 in the air, 2.4±1.3 in the NBO, and 2.3±1.4 in the HBO group (P<0.05 for HBO and NBO versus air; Kruskal–Wallis test, Mann–Whitney U-test, n=9/group).Figure 6
Figure 6Erythrocytic extravasation on trichrome-stained coronal brain sections at the level of the bregma +0.26 mm (anterior commissure) 24 hours after calcium-induced thromboemboli-middle cerebral artery occlusion without recanalization. (A) ...Hyperbaric Oxygen Attenuates Ischemia-Induced Matrix Metalloproteinase-9
To analyze the effect of oxygen therapy on MMP activity, protein extracts from brains collected 24 hours after TT-tMCAO were analyzed for MMP activity. Both MMP-9 (92 kDa) and MMP-2 (72 kDa) were observed as clear bands (Figure 5). At 24 hours after TT-tMCAO, MMP-2 levels did not differ between ischemic and nonischemic hemispheres in any group. However, MMP-9 levels in the ischemic hemisphere were distinctly higher than in the nonischemic hemisphere in all groups. Remarkably, when comparing the MMP-9 levels in the ischemic hemisphere among groups, HBO treatment resulted in a significant reduction in the MMP-9 band in the ischemic hemisphere in comparison to the air and NBO groups whereas NBO only tended to reduce MMP-9 levels. No differences were noted between MMP-9 bands after tMCAO in the nonischemic hemispheres among air-, NBO-, and HBO-treated mice (Figure 5).Go to:Discussion
This study provides several major new findings. (1) Oxygen therapy in combination with thrombolytic therapy only affects infarct size if recanalization is successful. (2) Both NBO and, more effectively, HBO reduce size and frequency of gross parenchymal hemorrhage after thrombolysis-induced reperfusion. (3) HBO and NBO reduce early BBB permeability after tMCAO, which is a marker for subsequent hemorrhagic complications of thrombolysis. (4) Oxygen therapy improves microvascular integrity even in regions that undergo parenchymal infarction.Secondary hemorrhage in ischemic stroke patients is stronger and occurs more frequently if the occluded cerebral artery is recanalized (Molina et al, 2001). Therefore, when experimentally testing the effect of an adjunctive therapy on cerebral hemorrhage after thrombolysis, it is desirable to control the recanalization effect of rt-PA. To appropriately model the variable effect of thrombolysis in patients in our study, two different clots were injected for tMCAO, and reperfusion was monitored using repetitive PW–MRI. Although rt-PA successfully recanalized the MCA in TT-tMCAO, vascular occlusion persisted despite thrombolysis in CT-tMCAO. Intriguingly, the effects of oxygen therapy in combination with rt-PA differed substantially between these two models. First, oxygen therapy reduced parenchymal damage in TT- but not in CT-tMCAO. This is consistent with most previous studies showing a cerebroprotective effect of early oxygen therapy in transient cerebral ischemia (Singhal et al, 2002; Veltkamp et al, 2005a, 2005b) but limited or no infarct size reduction after permanent MCAO (for review, see Helms et al, 2005; Poli and Veltkamp, 2009; Singhal, 2007). A limitation of this study is that neurologic function was not assessed.The primary goal of this study was to examine the effect of oxygen therapy on secondary hemorrhage after thrombolysis. In line with findings from Qin et al (2007), who reported a reduction of hemorrhagic transformation in rats treated with HBO compared with air after filament-induced MCAO, HBO reduced both macroscopic parenchymal hemorrhage in recanalized and and hemorrhagic transformation in permanent thromboembolic ischemia, respectively. Interestingly, NBO also reduced secondary hemorrhage in TT-tMCAO although its effect was less powerful and less consistent than that of HBO. In a previous experimental study similar to ours in which NBO was also administered before thrombolysis, NBO tended to reduce hemorrhage volume (Henninger et al, 2006, 2009). In another recent study, NBO coadministered with thrombolysis failed to decrease secondary hemorrhage after thromboembolic MCAO (Fujiwara et al, 2009). Different timing of thrombolysis and oxygen treatment may underlie the discrepancy in these results. A strength of our study is that our experimental setup frequently induced parenchymal hemorrhage after TT-MCAO, which is clinically more relevant than hemorrhagic transfomation. NBO tended to increase hemorrhagic transformation in a clinical pilot study (Singhal et al, 2005a) but this increase in petechial-type ‘asymptomatic' secondary hemorrhage was related to a higher rate of reperfusion.Our findings confirm a clear association between the effects of oxygen therapy on postischemic BBB permeability and on hemorrhage after thrombolysis. Topographic analysis of multimodal MRI showed that more than 95% of the hypointense T2* signal 24 hours after tMCAO was located within the area of intense postcontrast enhancement on T1w images at 2.5 hours after tMCAO. This is in accordance with previous experimental and clinical findings that early appearance of a circumscribed contrast enhancement on T1w shows tissue at risk for subsequent secondary hemorrhage (Kastrup et al, 2008; Neumann-Haefelin et al, 2002). Although an attenuation of postischemic BBB permeability in animals treated with NBO or HBO has been reported earlier (Liu et al, 2009; Qin et al, 2007; Veltkamp et al, 2005a), it was unclear as to whether this reflected a specific protective effect on cerebral microvessels or was proportional to overall parenchymal protection. As 95% of macroscopic hemorrhage on T2* MRI 24 hours after TT-tMCAO was located within the infarcted tissue (i.e., hyperintense area on DWI) in our experiments, oxygen therapy reduced secondary hemorrhage within the infarcted area. Thus, oxygen therapy had a beneficial effect on microvascular integrity despite its failing to protect the parenchyma. This protective effect on the microvasculature is further supported by our findings in permanent CT-tMCAO where oxygen therapy (in particular HBO) decreased histologic hemorrhagic transformation and hemoglobin content but did not reduce infarct size.The molecular mechanisms underlying the effects of oxygen therapy on the cerebral microvessels remain to be fully elucidated. Our findings are consistent with previous reports showing that oxygen therapy attenuates the activation of MMPs and reduces the digestion of basal lamina components and tight junction proteins (Kim et al, 2005; Liu et al, 2009; Singhal et al, 2002; Veltkamp et al, 2006b). We already showed that HBO reduces tissue hypoxia, and attenuates induction of hypoxia-inducible factor-1 and one of its target gene, the vascular permeability factor vascular endothelial growth factor (Sun et al, 2008). Furthermore, we recently showed that hypoxia-induced edema formation in the brain is mediated by MMP-9-dependent rearrangement and gap formation of tight junction proteins through a vascular endothelial growth factor-dependent mechanism (Bauer et al, 2009). Thus, our data suggest that HBO therapy can attenuate the activation of this hypoxia-permeability axis.In conclusion, our findings are of profound relevance for translational studies analyzing the usefulness of oxygen therapy in acute ischemic stroke. Whether oxygen therapy can reduce an ischemic brain lesion depends largely on successful, subsequent recanalization. As oxygen therapy also attenuates secondary hemorrhage within infarcted tissue, the most dreaded complication of recanalization therapy, combining it with thrombolytic therapy early on appears particularly promising. Despite some differences in efficacy, NBO and HBO could be viewed as complementary treatment strategies in the clinical setting (e.g., prehospital NBO followed by inhospital HBO).Go to:Acknowledgments
This work was supported by grants from the Deutsche Forschungsgemeinschaft (VE 196/2-2) and the GEMI fund. RV is supported by an Else-Kröner-Memorial Scholarship.Go to:Notes
The authors declare no conflict of interest.Go to:Footnotes
Supplementary Information accompanies the paper on the Journal of Cerebral Blood Flow and Metabolism website (http://www.nature.com/jcbfm)Go to:Supplementary Material
Supplementary Figure 1Click here for additional data file.(7.9M, tif)Supplementary Figure 2
Click here for additional data file.(7.9M, tif)Supplementary Figure 3
Click here for additional data file.(2.6M, tif)Supplementary Figure 4
Click here for additional data file.(361K, tif)Supplementary Figure Legends
Click here for additional data file.(21K, doc)Go to:References
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EECP RESEARCH

RESEARCH AND DATA ABOUT EECP STUDIES.
ECP THERAPY IS NOT NEW. IT IS SCIETNIFICALLY PROVEN AND US-FDA APPROVED FOR THE TREATMENT OF
1. STABLE ANGINA PECTORIS
2. UNSTABLE ANGINA PECTORIS
3. ACUTE MYOCARDIAL INFARCTION.
4. CARDIOGENIC SHOCK 5.CONGESTIVE HEART FAILURE.
6.RECENT STUDIES SHOW THAT ECP REVERSE THE VASCULAR
ENDOTHELIAL DYSFUNCTION.

CONTENTS:
1. EECP RESEARCH AND INTERNATIONAL REGISTRY PAGE 1.
2. HISTORY OF EECP PAGE 67
3. MULTIPLE CENTER STUDIES OF EECP PAGE 77
4. PEECH STUDIES OF EECP PAGE 100


EECP Research Lab
Ozlem Soran, M.D., MPH, FACC, FESC

As Director of the EECP Research Lab, Dr. Soran and her colleagues have recognized that EECP is safe and effective in patients with ischemic heart disease and compromised left ventricular function (J Cardiac Failure). This important observation led them to undertake a safety and efficacy study of EECP in patients with both ischemic and non-ischemic left ventricular dysfunction and heart failure (Congestive Heart Failure). Not only did EECP appear to improve outcomes in patients with both ischemic and non-ischemic myopathies, but also the benefits appeared to be persistent for up to 6 months after therapy. These findings lead the FDA to approve the use of EECP treatment in heart failure management on June 2002.
Based on these salutary effects of EECP in patients with left ventricular dysfunction, a multi-center clinical study, the PEECH Trial, (Prospective Evaluation of Enhanced External Counterpulsation (EECP) was begun in 2001. Dr. Soran is serving as a Principal Investigator for this study. The results of this study are expected to be published in 2006.
International EECP patient registry (IEPR);
Dr. Soran also serves as the primary investigator of International EECP Patient Registry (IEPR) and have been instrumental in organizing the International EECP Patient Registry with the Graduate School of Public Health Epidemiology data center. Currently, 5000 patients from over 90 centers are enrolled in this phase- I Registry. Additional 2500 patients have been enrolled to the phase-II. By using IEPR data, several publications have been made to fill the gaps that have not been answered by clinical trials.
Observation from this EECP registry is the beneficial effects of EECP in patients with coronary disease appear to persist for up to 1 year after treatment. This observation led her and her colleagues from across the country to hypothesize that the most likely mechanism for EECP's benefits was the development of collateral vessels in response to EECP-induced shear stress in the coronary arteries.
To test this hypothesis, Dr. Soran has participated in a pilot study with a group of highly prestigious investigators including Dr. George Beller, Chief of the Division of Cardiology at the University of Virginia, Dr. Anthony DeMaria, Chief of the Division of Cardiology at UCSD, and Dr. Richard Conti, Emeritus Chief of the Division of Cardiology at the University of Florida. Using state of the art imaging technology, they have obtained pilot data assessing the development of new vascular beds in the coronary circulation after EECP. If the final results support the initial hypothesis, this data will be used to support the submission of a NIH grant application.
Heart Failure Home Care Trial:
Dr. Soran has received a $2.8M grant from the Centers for Medicare and Medicaid Services (CMS) to conduct a 4-year study assessing the impact of the Alere Heart Failure monitoring system on clinical outcomes and the economics of care among Medicare beneficiaries representing underserved population including women and non-Caucasian men. Unique aspects of this project are that Medicare beneficiaries who are diagnosed with heart failure are being enrolled from a group of community-based primary care practices rather than University affiliated teaching hospitals. The study institutes an educational program for both physicians and patients to improve compliance with recent HFSA, AHA and ACC guidelines for heart failure and evaluates a group of heart failure patients that make up a major portion of the Medicare population who are largely ignored in most heart failure trials (i.e. women and non-Caucasian males). Enrollment began on April 2002.
Patients are being enrolled from three sites: The University of Pittsburgh, Case Western University, and the Mount Sinai Medical Center. Being the Primary Investigator for the Pittsburgh site and the director of the previously mentioned study sites allows the University of Pittsburgh/UPMC to play a pivotal role in this Medicare funded project.
This Web site is maintained by the Center for Research on Health Care (CRHC) Data Center.
Contact the webmaster at dcweb@pitt.edu.

Physiological considerations
One theory is that EECP exposes the coronary circulation to increased shear stress, and that this results in the production of a cascade of growth factors that result in angiogenesis.[5]
References.
^ Zheng ZS, Li TM, Kambic H, et al. (1983). "Sequential external counterpulsation (SECP) in China". Trans Am Soc Artif Intern Organs 29: 599–603. PMID 6673295.
^ a b Arora RR, Chou TM, Jain D, et al. (June 1999). "The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of ECP on exercise-induced myocardial ischemia and anginal episodes". J. Am. Coll. Cardiol. 33 (7): 1833–40. doi:10.1016/S0735-1097(99)00140-0. PMID 10362181.
^ Lawson WE, Hui JC, Zheng ZS, et al. (1996). "Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect?". Cardiology 87 (4): 271–5. doi:10.1159/000177103. PMID 8793157.
^ Werner D, Schneider M, Weise M, Nonnast-Daniel B, Daniel WG (October 1999). "Pneumatic external counterpulsation: a new noninvasive method to improve organ perfusion". Am. J. Cardiol. 84 (8): 950–2, A7–8. doi:10.1016/S0002-9149(99)00477-4. PMID 10532522.
^ Soran O, Crawford LE, Schneider VM, Feldman AM (March 1999). "Enhanced external counterpulsation in the management of patients with cardiovascular disease". Clin Cardiol 22 (3): 173–8. doi:10.1002/clc.4960220304. PMID 10084058.
Manchanda A, Soran O (October 2007). "Enhanced external counterpulsation and future directions: step beyond medical management for patients with angina and heart failure". J. Am. Coll. Cardiol. 50 (16): 1523–31. doi:10.1016/j.jacc.2007.07.024. PMID 17936150.







Research done:

Enhanced External Counterpulsation in the Management of Angina in the Elderly
Linnemeier G, Michaels AD, Soran O, Kennard ED; International EECP Registry (IEPR) Investigators.
American Journal of Geriatric Cardiology. 2003 Mar-Apr;12(2):90-6.

Ongoing and Planned Studies of Enhanced External Counterpulsation
Conti CR.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II26-28.

Treatment Options for Angina Pectoris and the Future Role of Enhanced External Counterpulsation
Holmes DR Jr.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II22-25.

Current Use of Enhanced External Counterpulsation and Patient Selection
Lawson WE.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II16-21.

Enhanced External Counterpulsation: Mechanism of Action
Feldman AM.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II11-15.

A Review of Enhanced External Counterpulsation Clinical Trials
Beller GA.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II6-10.

A Historical Overview of Enhanced External Counterpulsation
DeMaria AN.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II3-5.

Enhanced External Counterpulsation - A Therapeutic Option for Patients with Chronic Cardiovascular Problems
Linnemeier G.
Journal of Cardiovascular Management. 2002 Nov-Dec;13(6):20-25

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, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM.
Congestive Heart Failure. 2002 Nov-Dec;8(6):297-302.

Left Ventricular Systolic Unloading and Augmentation of Intracoronary Pressure and Doppler Flow During Enhanced External Counterpulsation
Michaels AD, Accad M, Ports TA, Grossman W.
Circulation 2002 Sep 3;106(10):1237-1242.

Experience with Enhanced External Counterpulsation (EECP) in Coronary Artery Disease
Crawford LE.
Today’s Therapeutic Trends. 2002;20(3):243-252.

Enhanced External Counterpulsation in Patients with Heart Failure: A Multicenter Feasibility Study
Soran O, Fleishman B, Demarco T, Grossman W, Schneider VM, Manzo K, de Lame PA, Feldman AM.
Congestive Heart Failure. 2002 Jul-Aug;8(4)204-8, 227.

Relation of the Pattern of Diastolic Augmentation During a Course of Enhanced External Counterpulsation (EECP) to Clinical Benefit [from the International EECP Patient Registry (IEPR]
Lakshmi MV, Kennard ED, Kelsey SF, Holubkov R, Michaels AD.
American Journal of Cardiology. 2002 Jun 1;89(11):1303-1305.

Comparison of Patients Undergoing Enhanced External Counterpulsation and Percutaneous Coronary Intervention for Stable Angina Pectoris
Holubkov R, Kennard ED, Foris JM, Kelsey SF, Soran O, Williams DO, Holmes Jr. DR.
The American Journal of Cardiology. 2002 May 15;89:1182-1186.

Effects of Enhanced External Counterpulsation on Stress Radionuclide Coronary Perfusion and Exercise Capacity in Chronic Stable Angina Pectoris
Stys TP, Lawson WE, Hui JCK, Fleishman B, Manzo K, Strobeck JE, Tartaglia J, Ramasamy S, Suwita R, Zheng ZS, Liang H, Werner D.
The American Journal of Cardiology. 2002 Apr 1;89(7):822-824.

Effects of Enhanced External Counterpulsation on Health-Related Quality of Life Continue 12 Months After Treatment: A Substudy of the Multicenter Study of Enhanced External Counterpulsation
Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto R, Ferrans CE, Keller S.
Journal of Investigative Medicine. 2002 Jan;50(1):25-32.

Acute and Chronic Hemodynamic Effects of Enhanced External Counterpulsation in Patients with Angina Pectoris
Arora RR, Carlucci ML, Malone AM, Baron NV.
Journal of Investigative Medicine. 2001 Nov;49(6):500-504.

Acute Hemodynamic Effects and Angina Improvement with Enhanced External Counterpulsation
Stys T, Lawson WE, Hui JCK, Lang G, Liuzzo J, Cohn PF.
Angiology. 2001 Oct;52(10):653-658.

A Report from the International Enhanced External Counterpulsation Registry (IEPR)
Holubkov R, Kennard E, Kelsey S, Soran O.
Advances in Coronary Artery Diseases-4th International Congress on Coronary Artery Disease. 2001 Oct 21-24;(Prague, Czech Republic):387-391.

Benefit and Safety of Enhanced External Counterpulsation in Treating Coronary Artery Disease Patients with a History of Congestive Heart Failure
Lawson WE, Kennard ED, Holubkov R, Kelsey SF, Strobeck JE, Soran O, Feldman AM.
Cardiology. 2001;96(2):78-84.

Changes in Ocular Blood Flow Velocities During External Counterpulsation in Healthy Volunteers and Patients with Atherosclerosis
Werner D, Michelson G, Harazny J, Michalk F, Voigt JU, Daniel WG.
Graefe’s Archive for Clinical and Experimental Ophthalmology. 2001 Aug;239(8):599-602.

Enhanced External Counterpulsation Improved Myocardial Perfusion and Coronary Flow Reserve in Patients with Chronic Stable Angina; Evaluation by 13N-Ammonia Positron Emission Tomography
Masuda D, Nohara R, Hirai T, Kataoka K, Chen LG, Hosokawa R, Inubushi M, Tadamura E, Fujita M, Sasayama S.
European Heart Journal. 2001 Aug;22(16):1451-1458.

Safety and Effectiveness of Enhanced External Counterpulsation in Improving Angioplasty Restenosis
Stys TP, Lawson WE, Hui JCK, Tartaglia JJ, Subramanian R, Du ZM, Zhang MQ.
Proceedings of the 2nd International Congress on Heart Disease – New Trends in Research, Diagnosis and Treatment (International Academy of Cardiology).. 2001 Jul 21-24;(Washington DC, USA):369-372.

Effects of Enhanced External Counterpulsation on Rennin-Angiotensin System on Experimental AMI
Lu L, Zheng ZS, Wu WK, Lawson WE, Hui JCK.
Proceedings of the 2nd International Congress on Heart Disease – New Trends in Research, Diagnosis and Treatment (International Academy of Cardiology). 2001 Jul 21-24;(Washington DC, USA):275-279.

Predictors of Adverse Outcomes in Treating Angina Patients with Enhanced External Counterpulsation
Lawson WE, Fleishman B, Manzo K, Kennard ED, Holubkov R, Kelsey SF.
Proceedings of the 2nd International Congress on Heart Disease – New Trends in Research, Diagnosis and Treatment (International Academy of Cardiology). 2001 Jul 21-24;(Washington DC, USA):231-234.

The International EECP Patient Registry (IEPR): Design, Methods, Baseline Characteristics and Acute Results
Barsness G, Feldman AM, Holmes Jr. DR, Holubkov R, Kelsey SF, Kennard ED.
Clinical Cardiology. 2001 Jun;24(6):435-442.

Does Higher Diastolic Augmentation Predict Clinical Benefit from Enhanced External Counterpulsation?: Data from the International EECP Patient Registry (IEPR)
Michaels AD, Kennard ED, Kelsey SE, Holubkov R, Soran O, Spence S, Chou TM.
Clinical Cardiology. 2001 Jun;24(6):453-458.

Numerical Simulation of Enhanced External Counterpulsation
Ozawa ET, Bottom KE, Xiao X, Kamm RD.
Annals of Biomedical Engineering. 2001 Apr;29(4):284-297.

Psychosocial Effects of Enhanced External Counterpulsation in the Angina Patient: A Second Study
Springer S, Fife A, Lawson W, Hui JCK, Jandorf L, Cohn PF, Fricchione G.
Psychosomatics. 2001 Mar-Apr;42(2):124-132.

Enhanced External Counterpulsation in Unrevascularizable Patients
Barsness GW.
Current Interventional Cardiology Reports. 2001 Feb;3(1):37-43.

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, Ikeda H, Ueno T, Matsumoto T, Murohara T, Imaizumi T.
Journal of the American College of Cardiology. 2001 Jan;37(1):93-99.

Enhanced External Counterpulsation for Chronic Myocardial Ischemia
Lawson WE, Hui JCK.
The Journal of Critical Illness. 2000 Nov;15(11):629-636.

Comparison of Hemodynamic Effects of Enhanced External Counterpulsation and Intra-Aortic Balloon Pumping in Patients with Acute Myocardial Infarction
Taguchi I, Ogawa K, Oida A, Abe S, Kaneko N, Sakio H.
The American Journal of Cardiology. 2000 Nov 15;86(10):1139-1141.

Treatment Benefit in the Enhanced External Counterpulsation Consortium
Lawson WE, Hui JCK, Lang G.
Cardiology. 2000;94(1):31-35.

Noninvasive Revascularization by Enhanced External Counterpulsation: A Case Study and Literature Review
Singh M, Holmes Jr. DR, Tajik AJ, Barsness GW.
Mayo Clinic Proceedings. 2000 Sep;75(9):961-965.

Long-Term Prognosis of Patients with Angina Treated with Enhanced External Counterpulsation: Five-Year Follow-Up Study
Lawson WE, Hui JCK, Cohn PF.
Clinical Cardiology. 2000 Apr;23(4):254-258.

Abstracts

Is Enhanced External Counterpulsation the Preferred Treatment for Chronic Stable Angina in Select Patients 75 Years and Older?
Linnemeier G, Kennard ED, Kelsey SF, Soran O.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(1162-86).

Two-Year Outcomes After Enhanced External Counterpulsation: Data From the International EECP Patient Registry
Michaels AD, Linnemeier G, Soran O, Kennard ED.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(1148-116).

Enhanced External Counterpulsation for the Relief of Angina in Patients With Diabetes: A One-Year Clinical Outcome Study
Linnemeier GC, Kennard ED, Soran O, Kelsey SF.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(1148-115).

Atrial Fibrillation Does Not Degrade the Clinical Benefits From Enhanced External Counterpulsation Therapy in Patients With Chronic Angina: Results From the International EECP Patient Registry
Ochoa AB, O'Neill WW, Almany S.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(1148-114).

Is Enhanced External Counterpulsation Effective for Angina Relief in Diabetic Patients Who Are Not Candidates for Transcatheter Intervention?
Linnemeier GC, Kennard ED, Soran O, Kelsey SF.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(1003-89).

Preserved Benefit of Enhanced External Counterpulsation in End Stage Ischemic Heart Disease
William E. Lawson, Gregory W. Barsness, Elizabeth D. Kennard, IEPR Investigators.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(829-4).

Enhanced External Counterpulsation Improves Endothelial Function in Patients With Coronary Artery Disease
Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Holmes, Jr. DR, Higano ST, Lerman A.
Journal of the American College of Cardiology. 2003 Mar 19;41(6 Suppl A):(829-3).


Diastolic Augmentation is an Independent Predictor of Improved Outcome in 3536 Patients Following Enhanced External Counterpulsation (EECP)
Brown A, Dodd D, Bagger P, Louis AA, Kennard ED, Kelsey SF, Horgan JH.
European Heart Journal. 2002 Aug;4(Abstr Suppl)567(2932).

Functional Status of Patients with Chronic Angina Treated with Enhanced External Counterpulsation
Kennard ED, Kelsey SF, Linnemeier G.
European Heart Journal. 2002 Aug;4(Abstr Suppl):619(3281).

Microvessel Angiogenesis Induced by Enhanced External Counterpulsation in the Chronic Expirement Infarct Model
Wu G, Zheng ZS, Du Z, Hu C, Zheng J, Fang D, Ma H, Lawson WE, Hui JCK.
Journal of Cardiac Failure 2002 Aug;8(4 Suppl 1):S26 (095).

Benefit of Enhanced External Counterpulsation in Coronary Patients with Left Ventricular Dysfunction: Cardiac or Peripheral Effect?
Lawson W, Pandey K, Hui J, Krishnamurthy S, D’Ambrosia D, Vilkas D, Maliszewski M.
Journal of Cardiac Failure 2002 Aug;8(4 Suppl 1):S41 (146).

Diabetic Patients with Angina Undergoing Enhanced External Counterpulsation Therapy – The Effect of Low Ejection Fraction
Linnemeier G, Kennard E, Kelsey S.
Journal of Cardiac Failure 2002 Aug;8(4 Suppl 1):S78 (325).

Do Women with Left Ventricular Dysfunction and Refractory Angina Respond as Well as Men to Enhanced External Counterpulsation?

Soran O, Kennard E, Feldman A.
Journal of Cardiac Failure 2002 Aug;8(4 Suppl 1):S79 (291).

Does Enhanced External Counterpuslation (EECP Reduce the Refractory Angina Burden in Patients with Left Ventricular Dysfunctio: - A 2 Year Follow-Up Study
Soran O, Kennard E, Feldman A.
Presented at the 8th World Congress on Heart Failure - Mechanisms and Management - International Academy of Cardiology. 2002 Jul 13-16;(Washington DC, USA).

Does a History of Congestive Heart Failure Influence the Effectiveness of Enhanced External Counterpulsation for the Treatment of Angina in Patients with Diabetes? A One Year Clinical Outcome Study from the International EECP Patient Registry
Linnemeier GC, Kennard ED, Rutter MK, Nesto RW.
Presented at Complications, Macrovascular. 2002 Jun 15.

Enhanced External Counterpulsation Provides Relief from Severe Angina in Diabetic Patients – A Six-Month Clinical Outcome Study from the International EECP Patient Registry
Linnemeier GC, Kennard ED, Lawson WE.
Presented at the British Cardiac Society. May 2002.

Does EECP Improve Cardiac Function in Ischemic Cardiomyopathy?
Suresh VD, Lawson W, Hui JCK, D’Ambrosia D.
Presented at The American Federation for Medical Research. 2002 Apr 12; (Baltimore, Maryland).

Safety and Efficacy of Enhanced External Counterpulsation in Hypertensive Patients with Refractory Angina Pectoris: Short-and Long-Term Follow-Up
Arora R, Orlando J, Malone A,Bejjanki R, Carlucci M, Kennard L.
Journal of the American College of Cardiology. 2002 Mar 6;39(5 Suppl A):255A(1154-80).

Enhanced External Counterpulsation Reduces Angina and Improves Quality of Life in Elderly Unrevascularizable Patients
Linnemeier G, Kennard E, Lawson WE.
Journal of the American College of Cardiology. 2002 Mar 6;39(5 Suppl A):175A(847-4).

Do Women with Refractory Angina Respond as Well as Men to Treatment with Enhanced External Counterpulsation?
Lawson WE, Kennard E, Linnemeier G, Holubkov R, Mehra M.
Journal of the American College of Cardiology. 2002 Mar 6;39(5 Suppl A):154A(808-2).

Enhanced External Counterpulsation Promotes Angiogenesis Factors in Patients with Chronic Stable Angina
Masuda D, Nohara R, Kataoka K, Hosokawa R, Kanbara N, Fujita M.
Circulation. 2001 Oct 23;104(17 Suppl II):444(2109).

Efficacy of Enhanced External Counterpulsation (EECP) for Patients who are not Candidates for Coronary Revascularization: Immediate and One-Year Clinical Outcomes from the International EECP Patient Registry
Michaels AD, Kelsey SF, Holubkov R, Kennard ED.
American Journal of Cardiology. 2001;88(5 Suppl 1):103G-104G.

Effect of Enhanced External Counterpulsation on Circulating and Tissue Angiotensin II in Experimental Myocardial Infarction
Lu L, Zheng ZS, Wu WK, Lawson WE, Hui JCK.
Journal of Cardiac Failure. 2001;7(3 Suppl 2):35(123).

Is Diastolic Augmentation an Important Predictor of Treatment Completion for Patients with Left Ventricular Dysfunction Undergoing Enhanced External Counterpulsation for Angina?
Soran O, Michaels AD, Kennard ED, Kelsey SF, Holubkov R, Feldman AM.
Journal of Cardiac Failure. 2001:7(3 Suppl 2):99(371).

What Factors Predict Congestive Heart Failure During Treatment of Angina Patients with Enhanced External Counterpulsation
Lawson WE, Kennard ED, Holubkov R, Roberts JC, Feldman AM, Strobeck J.
Journal of Cardiac Failure. 2001;7(3 Suppl 2):48(174).

Enhanced External Counterpulsation for the Treatment of Angina in the Elderly: Safety, Response, and Durability of Benefit
Linnemeier G, Lawson W, Kennard ED, Holubkov R.
European Heart Journal. 2001 Sep;22:642(P3514).

Beneficial Effects of EECP on the Rennin-Angiotensin System in Patients with Coronary Artery Disease
Lawson WE, Hui JCK, Lu L, Zheng ZS, Zhang MQ.
European Heart Journal. 2001 Sep;22:538(P2903).

Improvement in Exercise Tolerance Post Enhanced External Counterpulsation is Related to the Peak Diastolic Augmentation Obtained
Brown AS, Ho, E, Heavey D, Dodd D, Horgan JH.
European Heart Journal. 2001 Sep;22:173(P1034).

Safety and Effectiveness of Enhanced External Counterpulsation in Improving Angioplasty Restenosis
Stys TP, Lawson WE, Hui JCK, Tartaglia JJ, Subramanian R, Du ZM, Zhang MQ.
The Journal of Heart Disease. 2001 Jul;2(1):131(524).

Effects of Enhanced External Counterpulsation on Rennin-Angiotensin System in Experimental AMI
Lawson WE, Lu L, Zheng ZS, Wu WK, Hui JCK.
The Journal of Heart Disease. 2001Jul;2(1):97(388).

Predictors of Adverse Outcomes in Treating Angina Patients with Enhanced External Counterpulsation
Lawson WE, Fleishman B, Manzo K, Kennard ED, Holubkov R, Kelsey S.
The Journal of Heart Disease. 2001 Jul;2(1):92(366).

EECP Produces Angina Relief in Diabetic Patients Comparable to Non-Diabetic Patients – A Six-Month Follow-Up Study
Linnemeier G, Kennard E, Lawson, Holubkov R.
Diabetes. 2001;50(Suppl II):A159(642-P).

Efficacy of Enhanced External Counterpulsation in Experimental Myocardial Infarction: Histochemistry and Ultrastructure
Huang W, Chen Y, Zheng ZS, Zhong WF, Lawson WE, Hui JCK.
Heart . 2001;85(Suppl I):P39(114).

The Improvements in Exercise Tolerance Post Enhanced External Counterpulsation in Patients with Chronic Refractory Angina are Related to Diastolic Augmentation
Brown AS, Ho E, Heavey D, Dodd D, Horgan JHH.
Heart . 2001;85(Suppl I):P41(125).

Primary Utilization to Improve Myocardial Perfusion with Enhanced External Counterpulsation Revascularization (pumper)
Fitzgerald CP, Kennard ED, Lawson WE, Holubkov R.
Heart . 2001;85(Suppl I):P41(124).

Patients with Non-Cardiac Vascular Disease and Chronic Angina Benefit from Enhanced External Counterpulsation
Bazaz S, Kennard ED, Holubkov R, Dwyer N, Crawford L.
Journal of the American College of Cardiology. 2001 Feb;37(2 Suppl A):255A(1159-162).

Are the Initial Benefits of Enhanced External Counterpulsation Sustained at One Year?
Lawson WE, Hui JCK, Kennard ED, Holubkov R, Kelsey SF.
Journal of the American College of Cardiology. 2001 Feb;37(2 Suppl A):328A(1117-75).

Intervention for Stable Angina: A Multicenter Comparison of Consecutive Patients Undergoing Enhanced External Counterpulsation (EECP) and PCI
Holubkov R, Kennard ED, Kelsey SF, Soran O, Holmes DR.
Journal of the American College of Cardiology. 2001 Feb;37(2 Suppl A):328A(1117-76).

Enhanced External Counterpulsation for Chronic Angina is Associated with Improved Outcome at 6 Months
Barsness GW, Schnell T, Holmes DR.
Journal of the American College of Cardiology. 2001 Feb;37(2 Suppl A):328A(1117-101).

Intermittent Shear Stimuli by Enhanced External Counterpulsation (EECP) Restores Endothelial Function in Patients with Coronary Artery Disease
Urano H, Lida S, Fukami K, Sugano R, Satoh A, Kanaya S.
Circulation. 2000 Oct;102(18 Suppl 2):II-57(266).

The Safety and Efficacy of Enhanced External Counterpulsation as Therapy for Unstable Angina
Arora, RR, Timoney MF, Kennard ED, Peart B.
Circulation. 2000 Oct;102(18 Suppl 2):II-615(2982).

Predictors of Successful Response to Enhanced External Counterpulsation as Treatment of Angina Pectoris
Lawson WE, Kennard ED, Hui JCK, Holubkov R, Kelsey S.
Circulation. 2000 Oct;102(18 Suppl 2):II-689(3332).

Enhanced External Counterpulsation with Heparin Pretreatment Improves Exercise Capacity of Anginal Patients
Fujita M, Masuda D, Nohara R, Sasayama S.
3rd International Congress on Coronary Artery Disease - Prevention to Intervention. 2000 Oct 2-5;(Lyon, France):469.

Effect of Enhanced External Counterpulsation on Cranial and Abdominal Blood Flow
Karim S, Setiadji R, Santosa F, Suwita R..
3rd International Congress on Coronary Artery Disease - Prevention to Intervention. 2000;Oct 2-5;( Lyon, France):472.

Benefit and Safety of Enhanced External Counterpulsation in the Treatment of Ischemic Heart Disease with History of Congestive Heart Failure
Lawson WE, Hui, JC, Kennard ED, Holubkov R, Kelsey SF, Strobeck JE, Feldman AM.
Journal of Cardiac Failure. 2000 Sep;6(3):84(316).

Six Month Outcome of Patients with Left Ventricular Dysfunction Treated with Enhanced External Counterpulsation (EECP)
Soran OZ, Kennard ED, Holubkov R, Strobeck JE, Feldman AM.
Journal of Cardiac Failure. 2000;6(3):75(282).

Enhanced External Counterpulsation in Heart Failure Patients: Results of a Pilot Study
Soran OZ, DeMarco T, Crawford LE, Schneider V, de Lame PA, Fleishman B, Grossman W,
Feldman AM.
Journal of Cardiac Failure. 2000;6(3):48(180).

Six Month Outcome of Patients with Left Ventricular Dysfunction Treated with Enhanced External Counterpulsation for Chronic Angina
Soran OZ, Kennard ED, Holubkov R, Strobeck J, Feldman AM.
European Heart Journal. 2000;21:598(3261).

Does Optimal Diastolic Augmentation Predict Clinical Benefit from Enhanced External Counterpulsation (EECP)? Data from the International Enhanced External Counterpulsation Patient Registry
Michaels AD, Kennard ED. Kelsey S, Holubkov R, Spence S, Chou TM.
European Heart Journal. 2000;21:173(P1043).

Improved Stress Radionuclide Coronary Perfusion and Exercise Capacity After Enhanced External Counterpulsation
Stys TP, Lawson WE, Hui JCK, Fleishman B, Strobeck JE, Hartman RB, Tartaglia J, Suwita R, Liang H.
European Heart Journal. 2000;21:173(P1042).

Enhanced External Counterpulsation (EECP) is Not Associated with Vascular Endothelial Cell Proliferation and Function
Arora RR, Baron NV, Timoney MF, Chen HJ, Rabbani L.
Federation of American Societies for Experimental Biology: 2000;14(4):A15(126.1).

Acute and Chronic Hemodynamic Effects of Enhanced External Counterpulsation in Patients with Angina Pectoris
Arora RR, Baron NV, Timoney MF.
Federation of American Societies for Experimental Biology. 2000;14(4):A155(126.5).

Improvement in Left Ventricular Performance by Enhanced External Counterpulsation in Patients with Heart Failure
Gorscan III J. Crawford L, Soran O, Wang H, Severyn D, de Lame PA, Schneider V, Feldman AM.
Journal of the American College of Cardiology. 2000 Feb;35(2 Suppl A):230A(901-5).

The New Therapeutic Approach with Chronic Stable Angina: Evaluation of Myocardial Flow and Flow Reserve by N-13-Ammonia PET
Masuda D, Nohara R, Hirai T, Chen LG, Inubushi M, Tadamura E.
Circulation. 1999;100(18):I-732(3865).

Safety of Enhanced External Counterpulsation in Heart Failure Patients
Soran OZ, DeMarco T, Crawford LE, Schneider V, Levy F, de Lame PA, Gorscan III J, Benedict CR, Grossman W, Feldman AM.
Circulation. 1999;100(18):I-300(1567).

A Neurohormonal Mechanism for the Effectiveness of Enhanced External Counterpulsation
Wu GF, Qiang SZ, Zheng ZS, Zhang MQ, Lawson WE, Hui JCK.
Circulation. 1999;100(18):I-832(4390).

Enhanced External Counterpulsation is a Safe and Effective Treatment for Angina in Patients with Severe Left Ventricular Dysfunction
Strobeck JE, Reade R, Kennard ED, Kelsey SF, Soran O, Feldman AM.
Journal of Cardiac Failure. 1999 Sep;5(3 Suppl 1):72(268).

Efficacy and Safety of Enhanced External Counterpulsation in Mild to Moderate Heart Failure: A Preliminary Report
Soran OZ, DeMarco T, Crawford LE, Schneider V, de Lame PA, Grossman W, Feldman AM.
Journal of Cardiac Failure. 1999 Sep;5(3 Suppl 1):53(195).

External Counterpulsation Increases Capillary Density During Experimental Myocardial Infarction
Huang W, Chen Y, Zheng Z, Ahong WF.
European Heart Journal. 1999 Aug-Sep;20(Abstr Suppl):168(P1016).

Comparison of Prognostic Surveys Used in the Multicentre Study of Enhanced External Counterpulsation (MUST-EECP)
Cohn P, Arora RR, Chou TM, Jain P, Nesto W, Fleishman B, Crawford L, McKiernan I, Lawson W.
European Heart Journal. 1999 Aug-Sep;20(Abstr Suppl):479(2518).

Blood Flow Volume Increases in Cranial and Abdominal Arteries During EECP
Steiadji R, Klta H, Barat J.
European Heart Journal. 1999 Aug-Sep;20(Abstr Suppl):551(2890).

Enhanced External Counterpulsation Protects Coronary Artery Disease Patients from Future Cardiac Events
Karim S, Kasim M, Suwita R, Andaningsih I, Setiadji R.
The Journal of Heart Disease. 1999 May;1(1):223(889).

Hemodynamic Effects of Enhanced External Counterpulsation in Patients with Acute Myocardial Infarction
Taguchi I, Ogawa K, Oida A, Kuga H, Suzuki H, Nagao I, Kaneko N, Sakio H.
The Journal of Heart Disease. 1999 May;1(1):222(887).

Effect of Enhanced External Counterpulsation on Nitric Oxide Production in Coronary Disease
Qian X, Wu W, Zheng ZS, Zhan CY, Yu BY, Lawson WE, Hui JCK.
The Journal of Heart Disease. 1999 May;1(1):193(769).

Effect of Enhanced External Counterpulsation on Lipid Peroxidation in Coronary Disease
Qian X, Wu W, Zheng ZS, Yu BY, Lou HC, Lawson WE, Hui JCK.
The Journal of Heart Disease. 1999 May;1(1):116(462).

Results of the Multicenter Enhanced External Counterpulsation (MUST‑EECP) Outcomes Study: Quality of Life Benefits Sustained Twelve Months After Treatment
Arora RR, Chou TM, Jain D, Nesto RW, Fleishman B, Crawford L, McKiernan T.
Journal of the American College of Cardiology. 1999 Feb;33(2 Suppl A):339A(1065-162).

Beneficial Effects of Enhanced External Counterpulsation (EECP) are Independent of the Severity of Angina Pectoris: Results of the MUST-EECP Trial
Arora RR, Chou TM, Jain D, Nesto RW, Fleishman B, Crawford L, McKiernan T.
Journal of the American College of Cardiology. 1999 Feb;33(2 Suppl A):349A(1097-140).

Results of the Multicenter Enhanced External Counterpulsation (MUST‑EECP) Outcomes Study: Quality of Life Benefits Sustained Six Months After Treatment
Arora RR, Chou TM, Jain D, Nesto RW, Fleishman B, Crawford L, McKiernan T.
Circulation. 1998 Nov;98(17 Suppl):I-350(1838).

Importance of the Number of Patent Vessels in the Benefit Seen with Enhanced External Counterpulsation in Chronic Angina: Results of the MUST-EECP Trial
Chou TM, Arora RR, Jain D, Nesto R, Fleishman B, Crawford L, McKiernan T.
Circulation. 1998 Nov;98(17 Suppl):I‑350(1837).

Pneumatic External Counterpulsation: A New Treatment for Selected Patients with Symptomatic Coronary Artery Disease
Werner D, Freidel C, Kropp J, Weise M, Waltenberger J, Kranz A, Daniel WG.
European Heart Journal. 1998 Aug;19(Abstr Suppl)58(P509).
Circulation. 1998 Nov;98(17 Suppl):I-350(1839).

Quality of Life Benefits in the Enhanced External Counterpulsation Clinical Consortium
Lawson WE, Hui JCK, Lang G.
European Heart Journal. 1998 Aug;19(Abstr Suppl)57(P505).

The Treatment of Angina Pectoris Refractory to Revascularization Procedures Using Enhanced External Counterpulsation in a Multicentre Study (MUST-EECP)
Cohn PF, Arora RR, Chou T, Jain D, Nesto R, Fleishman B, Crawford L, McKiernan T, Burger L,
Lawson WE.
European Heart Journal 1998 Aug;19(Abstr Suppl)57(P506).

Blood Pressure Changes During External Counterpulsation
Werner D, Wonka F, Klinghammer L, Krinke HE, Daniel WG.
European Heart Journal. 1998 Aug;19(Abstr Suppl) 655(P3659).

Improvement of Renal Perfusion and Function by Pneumatic External Counterpulsation
Werner D, John A, Tragner T, Zhang H, Schneider M, Nonnast-Daniel B, Gross P, Daniel WG.
European Heart Journal 1998;19(Abstr Suppl)655(P3660).

Beneficial Effects of Enhanced External Counterpulsation (EECP) may not be Mediated by Changes in Myocardial Perfusion
Arora RR, Akinboboye O, Blitzer M, Lin JW, Cannon PJ, Bergmann S.
Journal of the American College of Cardiology. 1998 Feb;31(2 Suppl A):138A(1059-1131).

Results of the Multicenter Study of Enhanced External Counterpulsation (MUST-EECP): Clinical Benefits are Sustained at a Mean Follow-Up Time of One Year
Arora RR, Chou T, Jain D, Nesto R, Fleishman B, Crawford L, McKiernan T.
Journal of the American College of Cardiology. 1998 Feb;31(2 Suppl A):214A(859-2).

Effects of Enhanced External Counterpulsation on Internal Mammary Artery Flow: Comparison with Intraaortic Balloon Counterpulsation
Katz WE, Gulati V, Feldman AM, Crawford L, Peron M, Soran O, Gorscan III J.
Journal of the American College of Cardiology. 1998 Feb;31(2 Suppl A):85A(825-1).

Complementary Roles of Enhanced External Counterpulsation (EECP) and Bypass Surgery (CABG) in the Treatment of Coronary Artery Disease (CAD)
Lawson WE, Hui JCK, Guo T, Berger L, Cohn P.
Cath-Lab Digest. 1998;6(1):18.

Enhanced External Counterpulsation Improves Exercise Capability in Patients with Chronic Stable Angina
Tartaglia J, Stenerson JF, Fleishman BL, Chamey R.
Journal of the American College of Cardiology. 1998 Feb;31(2 Suppl A):491A(1214-109).

Effects of Enhanced External Counterpulsation in Stable Angina Pectoris on Left Ventricular Mass, Volume and Ejection Fraction Measured by 3D Echo
Arora RR, Zheng ZS, Akinboboye O, Blitzer M, Lee S, Maguire B, King DL.
Journal of Investigative Medicine. 1997;45(3):211A.

Results of the Multicenter Study of Enhanced External Counterpulsation (MUST- EECP): EECP Reduces Anginal Episodes and Exercise-Induced Myocardial Ischemia
Arora RR, Chou TM, Jain D, Nesto RW, Fleishman B, Crawford L, McKiernan T.
Circulation. 1997 Oct 21;96(8 Suppl):I-466.

Five Year Follow-Up of Morbidity and Mortality in 33 Angina Patients Treated with Enhanced External Counterpulsation
Lawson WE, Hui JCK, Burger L, Cohn P.
Journal of Investigative Medicine. 1997;45(3):212A.

Does Prior Myocardial Revascularization Predict which Patients will Benefit Most from Enhanced External Counterpulsation?
Lawson WE, Hui JCK, Zheng ZS, Burger L, Guo T, Soroff H, Cohn P.
Journal of Investigative Medicine. 1997;45(3):214A.

Triple Vessel Disease Patients Benefit from Enhanced External Counterpulsation Despite Stenotic Grafts
Lawson WE, Hui JCK, Burger L, Guo T, Oster Z, Katz J, Cohn PF.
Journal of Investigative Medicine. 1997;45(3):214A.

Maximizing the Hemodynamic Benefits of Enhanced External Counterpulsation
Suresh K, Simandl S, Lawson WE, Hui JCK, Lillis O, Burger L, Guo T, Cohn PF.
Journal of Investigative Medicine. 1997;45(3):213A.

Duplexsonographic Findings During Pneumatic External Counterpulsation
Schneider M, Werner D, Nonnast-Daniel B, Garlichs C, Schwarz T, Schellong S, Daniel WG.
Circulation. 1996 Oct 15;94(8 Suppl 1):I-608(3564).

Acute Hemodynamic Benefits of Enhanced External Counterpulsation
Suresh K, Simandl S, Lawson WE, Hui JCK, Guo T, Burger L, Soroff H, Cohn PF.
The Journal of the American College of Cardiology. 1996;27(2):22A.

Can Clinical Findings Predict which Patients will Benefit Most from Enhanced External Counterpulsation?
Lawson WE, Hui JCK, Zheng ZS, Burger L, Jiang L, Lillis O, Soroff H, Cohn PF.
Journal of Investigative Medicine. 1995;43(5):392A.

Benefits are Sustained at 3-Year Follow-Up in Patients who have been Treated with Enhanced External Counterpulsation
Lawson WE, Hui JCK, Zheng ZS, Zvi O, Katz J, Diggs P, Burger L, Cohn C, Soroff H, Cohn P.
The Journal of the American College of Cardiology. 1994 Feb;389A(794-4).

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EECP Case Studies References

List of references and studies about Enhanced External Counter Pulsation EECP ECP




1. “ECP utilizes pneumatic cuffs on the lower extremities to provide diastolic augmentation & systolic unloading of blood pressure in order to decrease the cardiac work & oxygen consumption while enhancing coronary blood flow. Recent trials have shown that regular application improves angina, exercise capacity and regional myocardial perfusion.”
-------------------------------------------------------Harrison’s principles of Int. medicine: Edition 16th, Vol. II, Page 1441

2. “External counter pulsation is another promising alternative treatment of refractory angina. Data suggest that ECP reduce the frequency of angina and the use of nitroglycerin and improves exercise tolerance and quality of life. In a randomized, double-blind, sham – controlled study of ECP for patients with chronic stable angina, counter pulsation was associated with an increase in time to ST segment depression during exercise testing and a reduction in angina. It also reduced the extent of ischemia detected with myocardial perfusion imaging.”
-----------------------------------------------Braunwald’s text book of Cardiovascular Medicine: Edition 7th, Page 1308

3. “Million of cases treated with ECP, illustrates the capacity of EECP into revascularization the heart and control symptoms in patients who have not benefited from balloon angioplasty or bypass surgery. The author describe a 58 year old man who required two separate bypass surgery, six rounds of angioplasty involving over 20 narrowing and multiple heart catheterization, 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.”
--------------------------------Enhanced External Counter pulsation as an Adjunct to Revascularization in Unstable Angina Lawson WE, Hui JCK, Oster ZH, et al. Clinical Cardiology 1997; 178-180.

4.STONY BROOK TRIALS:
Open label studies on the safely and effectiveness of EECP in patient with chronic stable angina pectoris were conducted at the State University of New York at Stony Brook, beginning in1989 and was reported by Lawson el at in American Journal of Cardiology in 1992. All of those patients had incapacitating symptoms, refractory to medical therapy and external myocardial ischemia documented by thallium-201 perfusion imaging. All patients in this study showed a substantial improvement in symptoms with most reporting a complete absence of angina during normal activity. In addition, the majority of patients in this study showed a reduction in myocardial ischemia, with two-thirds demonstrating a complete absence of reversible defects. These results were accompanied by a significant increase in the mean duration of exercise during maximal stress testing of between 95 and 112 seconds.

5. INTERNATIONAL EECP PATIENT REGISTRY (IEPR):
In 1988, the International EECP Patient registry (IEPR) was established to document patient and characteristic for those undergoing EECP therapy, the safely and efficacy of EECP therapy and the therapy’s long term outcomes in the broader population. More than 6000 patients had been enrolled in the registry. An analysis of long-term outcomes suggests that the clinical benefits achieved are sustained upto three years following an initial course of treatment.

6. MUST EECP STUDY:
In 1995, a large randomized, controlled and double blinded multicentre trial on the efficiency of EECP in patients with chronic stable angina (MUST-EECP) was undertaken at seven leading university hospitals in the United States. The MUST EECP trial results were published in the Journal of the American Cardiology in June 1999”. A total of 139 patients were enrolled in this study and randomly assigned to active or sham group. Those assigned to the active group were given full pressure. Those randomized to the sham group were treated with low pressure. Patients enrolled in study ranged from 18-21 years of age, were classified as having DDS’ Class 1, 2, or 3 angina and had documented coronary artery disease, including a positive exercise stress test within 4 weeks of beginning EECP therapy.

Patient in the active EECP group demonstrated significantly increased time to exercise induced ST segment depression when compared to sham and baseline. Those in the active EECP group reported a significant decrease in the frequency of angina counts. Exercise duration increased significantly in both group but was greater in the active EP group.

7. OTHER STUDIES:
A study published in 2001 in the journal of American Collage of Cardiology by Urano at al. of Kurume University in Japan confirmed once more the benefits of EECP reported in the literature to date, a decline in anginal frequency, an increase in exercise capacity and a decrease in exercise induced in signs of myocardial ischemia. Additionally this study provides clear evidence that EECP improves diastolic filling in patients with coronary artery disease. The study showed that both the peak filling rate and the time to peak filling improved significantly. These indicators of improved cardiac function were also reflected in decreased levels of brain is secreted mainly by the left ventricle in response to stress and is a sensitive measure of cardiac function.

Here are some more links to case studies about EECP.

EECP Case Studies

Manchanda A, Soran O.
Enhanced external counterpulsation and future directions: step beyond medical management for patients with angina and heart failure.
J Am Coll Cardiol. 2007 Oct 16;50(16):1523-31. Epub 2007 Oct 1.

May O.
Residual high-grade angina after enhanced external counterpulsation therapy.
Cardiovasc Revasc Med. 2007 Jul-Sep;8(3):161-5.

Arora RR, Shah AG.
The role of enhanced external counterpulsation in the treatment of angina and heart failure.
Can J Cardiol. 2007 Aug;23(10):779-81. Review.

El-Sakka AI, Morsy AM, Fagih BI.
Enhanced external counterpulsation in patients with coronary artery disease-associated erectile dysfunction. Part II: impact of disease duration and treatment courses.
J Sex Med. 2007 Sep;4(5):1448-53. Epub 2007 Jul 18.

Werner D, Michalk F, Hinz B, Werner U, Voigt JU, Daniel WG.
Impact of enhanced external counterpulsation on peripheral circulation.
Angiology. 2007 Apr-May;58(2):185-90.

Lawson WE, Hui JC, Kennard ED, Soran O, McCullough PA, Kelsey SF; for the IEPR Investigators.
Effect of enhanced external counterpulsation on medically refractory angina patients with erectile dysfunction.
Int J Clin Pract. 2007 May;61(5):757-62.

El-Sakka A, Morsy A, Fagih B.
Enhanced external counterpulsation in patients with coronary artery disease-associated erectile dysfunction. Part I: effects of risk factors.
J Sex Med. 2007 May;4(3):771-9. Epub 2007 Apr 13.

Soran O, Kennard ED, Bart BA, Kelsey SF; IEPR Investigators.
Impact of external counterpulsation treatment on emergency department visits and hospitalizations in refractory angina patients with left ventricular dysfunction.
Congest Heart Fail. 2007 Jan-Feb;13(1):36-40. Erratum in: Congest Heart Fail. 2007 Mar-Apr;13(2):124.

Michaels AD, McCullough PA, Soran OZ, Lawson WE, Barsness GW, Henry TD, Linnemeier G, Ochoa A, Kelsey SF, Kennard ED.
Primer: practical approach to the selection of patients for and application of EECP.
Nat Clin Pract Cardiovasc Med. 2006 Nov;3(11):623-32. Review.

Feldman AM, Silver MA, Francis GS, Abbottsmith CW, Fleishman BL, Soran O, de Lame PA, Varricchione T; PEECH Investigators.
Enhanced external counterpulsation improves exercise tolerance in patients with chronic heart failure.
J Am Coll Cardiol. 2006 Sep 19;48(6):1198-205. Epub 2006 Aug 28.

Pettersson T, Bondesson S, Cojocaru D, Ohlsson O, Wackenfors A, Edvinsson L.
One year follow-up of patients with refractory angina pectoris treated with enhanced external counterpulsation.
BMC Cardiovasc Disord. 2006 Jun 15;6:28.

Silver MA.
Mechanisms and evidence for the role of enhanced external counterpulsation in heart failure management.
Curr Heart Fail Rep. 2006 Apr;3(1):25-32. Review.

Lawson WE, Hui JC, Kennard ED, Kelsey SF, Michaels AD, Soran O; International Enhanced External Counterpulsation Patient Registry Investigators.
Two-year outcomes in patients with mild refractory angina treated with enhanced external counterpulsation.
Clin Cardiol. 2006 Feb;29(2):69-73.

Loh PH, Louis AA, Windram J, Rigby AS, Cook J, Hurren S, Nikolay NP, Caplin J, Cleland JG.
The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina.
J Intern Med. 2006 Mar;259(3):276-84.

Soran O, Kennard ED, Kfoury AG, Kelsey SF; IEPR Investigators.
Two-year clinical outcomes after enhanced external counterpulsation (EECP) therapy in patients with refractory angina pectoris and left ventricular dysfunction (report from The International EECP Patient Registry).
Am J Cardiol. 2006 Jan 1;97(1):17-20. Epub 2005 Nov 2.

Michaels AD, Barsness GW, Soran O, Kelsey SF, Kennard ED, Hui JC, Lawson WE; International EECP Patient Registry Investigators.
Frequency and efficacy of repeat enhanced external counterpulsation for stable angina pectoris (from the International EECP Patient Registry).
Am J Cardiol. 2005 Feb 1;95(3):394-7.

Bonetti PO, Holmes DR Jr, Lerman A, Barsness GW.
Enhanced external counterpulsation for ischemic heart disease: what's behind the curtain?
J Am Coll Cardiol. 2003 Jun 4;41(11):1918-25. Review.

Soran O, Crawford LE, Schneider VM, Feldman AM.
Enhanced external counterpulsation as a new treatment modality for patients with erectile dysfunction.
Urol Int. 1998;61(3):168-71.

Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto RW.
The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
J Am Coll Cardiol. 1999 Jun;33(7):1833-40.

Lawson WE, Hui JC, Cohn PF.
Long-term prognosis of patients with angina treated with enhanced external counterpulsation: five-year follow-up study.
Clin Cardiol. 2000 Apr;23(4):254-8.

Lawson WE, Hui JC, Soroff HS, Zheng ZS, Kayden DS, Sasvary D, Atkins H, Cohn PF.
Efficacy of enhanced external counterpulsation in the treatment of angina pectoris.
Am J Cardiol. 1992 Oct 1;70(9):859-62.

Few More are here



For more insight into ECP, refer to internet. Type “EECP” in any of the search engine to get an access to more then 1 lac clinical sites.

Enhanced External Counterpulsation Does Not Compromise Cerebral Autoregulation
Marthol H, Werner D, Brown CM, Hecht M, Daniel WG, Hilz MJ.
Acta Neurologica Scandinavica. 2005 Jan:111(1):34-41.

Enhanced External Counterpulsation Does Not Alter Arterial Stiffness in Patients with Angina
Dockery F, Rajkumar C, Bulpitt CJ, Hall RJ, Bagger JP.
Clinical Cardiology. 2004 Dec;27:689-692.

Effects of Enhanced External Counterpulsation on Hemodynamics and its Mechanism
Taguchi I, Ogawa K, Kanaya T, Matsuda R, Kuga H, Nakatsugawa M.
Circulation Journal. 2004 Nov;68(11):1030-1034.

Angina Pectoria: A Review of Current and Emerging Therapies
Parker JO.
American Journal of Managed Care. 2004 Oct;10(11 Suppl):S332-338.

Current and Future Treatment Strategies for Refractory Angina
Yang EH, Barsness GW, Gersh BJ, Chandrasekaran K, Lerman A.
Mayo Clinic Proceedings. 2004 Oct;79(10):1284-1292.

Enhanced External Counterpulsation
Brosche TA, Middleton, SK, Boogaard RG.
Dimensions of Critical Care Nursing. 2004 Sep/Oct;23(5):208-213.

Effectiveness of Enhanced External Counterpulsation in Patients with Left Main Disease and Angina
Lawson WE, Hui JC, Barsness GW, Kennard ED, Kelsey SF; IEPR Investigators.
Clinical Cardiology . 2004 Aug;27(8):459-63.
Accelerated Reperfusion of Poorly Perfused Retinal Areas in Central Retinal Artery Occlusion and Branch Retinal Artery Occlusion After a Short Treatment with Enhanced External Counterpulsation
Werner D, Michalk F, Harazny J, Hugo C, Daniel WG, Michelson G.
Retina . 2004 Aug;24(4):541-547.

Enhanced External Counterpulsation Therapy: Significant Clinical Improvement without Electrophysiologic Remodeling
Henrickson CA, Chandra-Strobos N
Annals of Noninvasive Electrocardiology. 2004 Jul;9(3):265-269.

Enhanced External Counterpulsation Improves Skin Oxygenation and Perfusion
Hilz MJ, Werner D, Marthol H, Flachskampf FA, Daniel WG.
European Journal of Clinical Investigation. 2004 Jun;34(6):385-91.

Successful Treatment of Symptomatic Coronary Endothelial Dysfunction with Enhanced External Counterpulsation

Bonetti PO, Gadasalli SN, Lerman A, Barsness GW.
Mayo Clinic Proceedings. 2004 May;79(5):690-692.

Enhanced External Counterpulsation in Ischemic Heart Disease and Congestive Heart Failure
Mielniczuk L, da Silva LB, Haddad H.
Canadian Medical Association Journal. 2004 Apr 13;170(8):1223-1224.

Improvement of Oxygen Metabolism in Ischemic Myocardium as a Result of Enhanced External Counterpulsation with Heparin Pretreatment for Patients with Stable
Masuda D, Fujita M, Nohara R, Matsumori A, Sasayama S.
Heart Vessels. 2004 Mar;19(2):59-62.

Effect of Enhanced External Counterpulsation on Dobutamine-induced Left Ventricular Wall Motion Abnormalities in Severe Chronic Angina Pectoris
Bagger JP, Hall RJ, Koutroulis G, Nihoyannopoulos P.
American Journal of Cardiology. 2004 Feb 15;93(4):465-467.

Two-Year Outcomes After Enhanced External Counterpulsation for Stable Angina Pectoris
(from the International Patient Registry [IEPR])
Michaels AD, Linnemeier G, Soran O, Kelsey SF, Kennard ED.
American Journal of Cardiology. 2004 Feb 15;93(4):461-464.

A New Treatment Modality in Heart Failure Enhanced External Counterpulsation (EECP®)
Soran O.
Cardiology in Review. 2004 Jan-Feb;12(1):15-20.

Enhanced External Counterpulsation as Initial Revascularization Treatment for Angina
Refractory to Medical Therapy
Fitzgerald CP, Lawson WE, Hui JC, Kennard ED; IEPR Investigators.
Cardiology. 2003 Nov;100(3):129-35

Functional Status Improvement After Enhanced External Counterpulsation (EECP®) for Treatment of Chronic Angina Pectoris
Kennard ED, Linnemeier G, Kelsey SF.
Proceedings of the 5th International Congress on Coronary Artery Disease –Frontiers in Coronary Artery Disease. 2003 Oct 19-21;(Florence, Italy):187-190.

Comparison of 6 Months Clinical Outcomes, Event Free Survival Rates of Patients Undergoing Enhanced External Counterpulsation (EECP) for Coronary Artery Disease with Left Ventricular Dysfunction (LVD) in the United States and Europe
Soran O, Kennard ED, Kelsey SF.
Proceedings of the 5th International Congress on Coronary Artery Disease –Frontiers in Coronary Artery Disease. 2003 Oct 19-21;( Florence , Italy ):187-190(1205.00)

Enhanced External Counterpulsation for the Relief of Angina in Patients with Diabetes: Safety, Efficacy and 1-Year Clinical Outcomes
Linnemeier G, Rutter MK, Barsness G, Kennard ED, Nesto RW; IEPR Investigators.
American Heart Journal. 2003 Sep;146(3):453-458.

Analysis of Baseline Factors Associated with Reduction in Chest Pain in Patients with Angina Pectoris Treated by Enhanced External Counterpulsation
Lawson WE, Kennard ED, Hui JCK, Holubkov R, Kelsey SF.
The American Journal of Cardiology. 2003 Aug 15;92(4):439-443.

Enhanced External Counterpulsation for Refractory Angina Pectoris
Sinvhal RM, Gowda RM, Khan IA.
Heart. 2003 Aug;89(8):830-833.

Enhanced External Counterpulsation for Ischemic Heart Disease: What’s Behind the Curtain?
Bonetti PO, Holmes DR Jr, Lerman A, Barsness GW.
Journal of the American College of Cardiology. 2003 Jun 4;41(11):1918-1925.

Exercise Capability and Myocardial Perfusion in Chronic Angina Patients Treated with Enhanced External Counterpulsation
Tartaglia J, Stenerson Jr J, Charney R, Ramasamy S, Fleishman BL, Gerardi P, Hui JCK.
Clinical Cardiology. 2003 Jun;(26):287-290.

Changes of Cerebral Blood Flow Velocities During Enhanced External Counterpulsation
Werner D, Marthol H, Brown CM, Daniel WG, Hilz MJ.
Acta Neurologica Scandinavica. 2003 Jun;107(6):405-411.

Enhanced External Counterpulsation Improves Endothelial Function in Patients with Symptomatic Coronary Artery Disease
Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A.
Journal of the American College of Cardiology. 2003 May 21;41(10):1761-1768.

Enhanced External Counterpulsation in the Management of Angina in the Elderly
Linnemeier G, Michaels AD, Soran O, Kennard ED; International EECP® Registry (IEPR) Investigators.
American Journal of Geriatric Cardiology. 2003 Mar-Apr;12(2):90-6.

Enhanced External Counterpulsation
Lam L, Mahmood S.
Asian Cardiovascular & Thoracic Annals. 2003 Mar;11(1):92-94.


A Historical Overview of Enhanced External Counterpulsation
DeMaria AN.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II3-5.

A Review of Enhanced External Counterpulsation Clinical Trials
Beller GA.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II6-10.

Enhanced External Counterpulsation: Mechanism of Action
Feldman AM.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II11-15.

Current Use of Enhanced External Counterpulsation and Patient Selection
Lawson WE.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II16-21.

Treatment Options for Angina Pectoris and the Future Role of Enhanced External Counterpulsation
Holmes DR Jr.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II22-25.

Ongoing and Planned Studies of Enhanced External Counterpulsation
Conti CR.
Clinical Cardiology. 2002 Dec;25(12 Suppl 2):II26-28.

Enhanced External Counterpulsation - A Therapeutic Option for Patients with
Chronic Cardiovascular Problems
Linnemeier G.
Journal of Cardiovascular Management. 2002 Nov-Dec;13(6):20-25.

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, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM.
Congestive Heart Failure. 2002 Nov-Dec;8(6):297-302.

Left Ventricular Systolic Unloading and Augmentation of Intracoronary Pressure and Doppler Flow During Enhanced External Counterpulsation
Michaels AD, Accad M, Ports TA, Grossman W.
Circulation. 2002 Sep 3;106(10):1237-1242.

Experience with Enhanced External Counterpulsation (EECP®) in Coronary Artery Disease
Crawford LE.
Today’s Therapeutic Trends. 2002;20(3):243-252.

Enhanced External Counterpulsation in Patients with Heart Failure: A Multicenter Feasibility Study
Soran O, Fleishman B, Demarco T, Grossman W, Schneider VM, Manzo K, de Lame PA,
Feldman AM.
Congestive Heart Failure. 2002 Jul-Aug;8(4)204-8, 227.

Relation of the Pattern of Diastolic Augmentation During a Course of Enhanced External Counterpulsation (EECP®) to Clinical Benefit [from the International EECP® Patient Registry (IEPR)]
Lakshmi MV, Kennard ED, Kelsey SF, Holubkov R, Michaels AD.
American Journal of Cardiology. 2002 Jun 1;89(11):1303-1305.

Comparison of Patients Undergoing Enhanced External Counterpulsation and Percutaneous Coronary Intervention for Stable Angina Pectoris
Holubkov R, Kennard ED, Foris JM, Kelsey SF, Soran O, Williams DO, Holmes Jr. DR.
The American Journal of Cardiology. 2002 May 15;89:1182-1186.

Effects of Enhanced External Counterpulsation on Stress Radionuclide Coronary Perfusion and Exercise Capacity in Chronic Stable Angina Pectoris
Stys TP, Lawson WE, Hui JCK, Fleishman B, Manzo K, Strobeck JE, Tartaglia J, Ramasamy S, Suwita R, Zheng ZS, Liang H, Werner D.
The American Journal of Cardiology. 2002 Apr 1;89(7):822-824.

Effects of Enhanced External Counterpulsation on Health-Related Quality of Life Continue 12 Months After Treatment: A Substudy of the Multicenter Study of Enhanced External Counterpulsation
Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto R, Ferrans CE, Keller S.
Journal of Investigative Medicine. 2002 Jan;50(1):25-32.

Acute and Chronic Hemodynamic Effects of Enhanced External Counterpulsation in Patients with Angina Pectoris
Arora RR, Carlucci ML, Malone AM, Baron NV.
Journal of Investigative Medicine. 2001 Nov;49(6):500-504.

Acute Hemodynamic Effects and Angina Improvement with Enhanced External Counterpulsation
Stys T, Lawson WE, Hui JCK, Lang G, Liuzzo J, Cohn PF.
Angiology. 2001 Oct;52(10):653-658.

A Report from the International Enhanced External Counterpulsation Registry (IEPR)
Holubkov R, Kennard E, Kelsey S, Soran O.
Advances in Coronary Artery Diseases-4th International Congress on Coronary Artery Disease.
2001 Oct 21-24;(Prague, Czech Republic):387-391.

Benefit and Safety of Enhanced External Counterpulsation in Treating Coronary Artery Disease Patients with a History of Congestive Heart Failure
Lawson WE, Kennard ED, Holubkov R, Kelsey SF, Strobeck JE, Soran O, Feldman AM.
Cardiology. 2001;96(2):78-84.

Changes in Ocular Blood Flow Velocities During External Counterpulsation in Healthy Volunteers and Patients with Atherosclerosis
Werner D, Michelson G, Harazny J, Michalk F, Voigt JU, Daniel WG.
Graefe’s Archive for Clinical and Experimental Ophthalmology. 2001 Aug;239(8):599-602.

Enhanced External Counterpulsation Improved Myocardial Perfusion and Coronary Flow Reserve in Patients with Chronic Stable Angina; Evaluation by 13N-Ammonia Positron Emission Tomography
Masuda D, Nohara R, Hirai T, Kataoka K, Chen LG, Hosokawa R, Inubushi M, Tadamura E, Fujita M, Sasayama S.
European Heart Journal. 2001 Aug;22(16):1451-1458.

Safety and Effectiveness of Enhanced External Counterpulsation in Improving Angioplasty Restenosis
Stys TP, Lawson WE, Hui JCK, Tartaglia JJ, Subramanian R, Du ZM, Zhang MQ.
Proceedings of the 2nd International Congress on Heart Disease – New Trends in Research, Diagnosis and Treatment (International Academy of Cardiology).. 2001 Jul 21-24;(Washington DC, USA):369-372.

Effects of Enhanced External Counterpulsation on Rennin-Angiotensin System on Experimental AMI
Lu L, Zheng ZS, Wu WK, Lawson WE, Hui JCK.
Proceedings of the 2nd International Congress on Heart Disease – New Trends in Research, Diagnosis and Treatment (International Academy of Cardiology).2001 Jul 21-24;(Washington DC, USA):275-279.

Predictors of Adverse Outcomes in Treating Angina Patients with Enhanced External Counterpulsation
Lawson WE, Fleishman B, Manzo K, Kennard ED, Holubkov R, Kelsey SF.
Proceedings of the 2nd International Congress on Heart Disease – New Trends in Research, Diagnosis and Treatment (International Academy of Cardiology). 2001 Jul 21-24;(Washington DC, USA):231-234.

The International EECP® Patient Registry (IEPR): Design, Methods, Baseline Characteristics
and Acute Results
Barsness G, Feldman AM, Holmes Jr. DR, Holubkov R, Kelsey SF, Kennard ED.
Clinical Cardiology. 2001 Jun;24(6):435-442.

Does Higher Diastolic Augmentation Predict Clinical Benefit from Enhanced External Counterpulsation?: Data from the International EECP® Patient Registry (IEPR)
Michaels AD, Kennard ED, Kelsey SE, Holubkov R, Soran O, Spence S, Chou TM.
Clinical Cardiology. 2001 Jun;24(6):453-458.

Numerical Simulation of Enhanced External Counterpulsation
Ozawa ET, Bottom KE, Xiao X, Kamm RD.
Annals of Biomedical Engineering. 2001 Apr;29(4):284-297.

Psychosocial Effects of Enhanced External Counterpulsation in the Angina Patient: A Second Study
Springer S, Fife A, Lawson W, Hui JCK, Jandorf L, Cohn PF, Fricchione G.
Psychosomatics. 2001 Mar-Apr;42(2):124-132.

Enhanced External Counterpulsation in Unrevascularizable Patients
Barsness GW.
Current Interventional Cardiology Reports. 2001 Feb;3(1):37-43.

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, Ikeda H, Ueno T, Matsumoto T, Murohara T, Imaizumi T.
Journal of the American College of Cardiology. 2001 Jan;37(1):93-99.

Enhanced External Counterpulsation for Chronic Myocardial Ischemia
Lawson WE, Hui JCK.
The Journal of Critical Illness. 2000 Nov;15(11):629-636.

Comparison of Hemodynamic Effects of Enhanced External Counterpulsation and Intra-Aortic Balloon Pumping in Patients with Acute Myocardial Infarction
Taguchi I, Ogawa K, Oida A, Abe S, Kaneko N, Sakio H.
The American Journal of Cardiology. 2000 Nov 15;86(10):1139-1141.

Treatment Benefit in the Enhanced External Counterpulsation Consortium
Lawson WE, Hui JCK, Lang G.
Cardiology. 2000;94(1):31-35.

Noninvasive Revascularization by Enhanced External Counterpulsation:
A Case Study and Literature Review
Singh M, Holmes Jr. DR, Tajik AJ, Barsness GW.
Mayo Clinic Proceedings. 2000 Sep;75(9):961-965.

Long-Term Prognosis of Patients with Angina Treated with Enhanced External Counterpulsation: Five-Year Follow-Up Study
Lawson WE, Hui JCK, Cohn PF.
Clinical Cardiology. 2000 Apr;23(4):254-258.

Heparin and Angiogenic Therapy
Fujita M.
European Heart Journal. 2000 Feb;21(4):270-274.

EECP® Therapy Continues to Demonstrate Potential as a Treatment for Chronic Angina
Lang M.
Cardiovascular Disease Management. 1999 Nov.

Pneumatic External Counterpulsation: A New Noninvasive Method to Improve Organ Perfusion
Werner D, Schneider M, Weise M, Nonnast-Daniel B, Daniel WG.
The American Journal of Cardiology. 1999 Oct 15;84(8):950-952

External Counterpulsation Increases Capillary Density During Experimental Myocardial Infarction
Huang W, Chen YC, Zheng ZS, Zhong WF, Lawson W, Hui J.
Reprinted from the International Proceedings Division of the XXI Congress of the European Society
of Cardiology. 1999 Aug 28-Sep 1; Barcelona, Spain:349-353.

Enhanced External Counterpulsation: The Howard County Experience in the First 18 Patients
Gloth S, Oken HA.
Maryland Medical Journal. 1999 Jul-Aug;48(4):155-156.

Enhanced External Counterpulsation
Caldwell CR, St. Pierre M, Talley JD.
Journal of the Arkansas Medical Society. 1999 Jul;96(2):54‑56.

Treatment of Stable Angina
Thadani U.
Current Opinion in Cardiology. 1999 Jul;14(4):349-358.
The Multicenter Study of Enhanced External Counterpulsation (MUST-EECP®): Effect of EECP® on Exercise-Induced Myocardial Ischemia and Anginal Episodes
Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto R.
The Journal of the American College of Cardiology. 1999 Jun;33(7):1833-1840.

Improvement of Regional Myocardial and Coronary Blood Flow Reserve in a Patient Treated with Enhanced External Counterpulsation: Evaluation by Nitrogen-13 Ammonia PET
Masuda D, Nohara R, Inada H, Hirai T, Li-Guang C, Kanda H, Inubushi M, Tadamura E, Fujita M, Sasayama S.
Japanese Circulation Journal. 1999 May;63(5):407-411.

Enhanced External Counterpulsation in the Management of Patients with Cardiovascular Disease
Soran O, Crawford LE, Schneider VM, Feldman AM.
Clinical Cardiology. 1999 Mar;22(3):173-178.

Emerging Treatments for Refractory Angina
Cohn PF.
American College of Cardiology - Current Journal Review. 1999;Jan 2;8(1):44-46.

Enhanced External Counterpulsation as a New Treatment Modality for Patients with
Erectile Dysfunction
Froschermaier SE, Werner D, Leike S, Schneider M, Waltenberger J, Daniel WG, Wirth MP.
Urologia Internationalis. 1998;61(3):168-171.

Prior Revascularization Increases the Effective





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