ATHENA Clinical Trial Shows that Fat-Based Stem Cell Mixture Improves Heart Patient’s Health, But Does Not Improve Ejection Fraction.


The ATHENA trial is a clinical trial designed to test the ability of a patient’s own “adipose-derived regenerative cells” or ADRCs to improve to improve their heart function. In this trial, heart disease patients received injections of their own ADRCs into their heart muscle. Then these patients were followed and their symptoms, rates of hospitalizations, and heart function were monitored over a period of several months. The initial plans were to examine each patient at one week and at one, three, six, and twelve months after the procedure, and to interview patients via telephone calls from study staff two, three, four, and five years after the procedure.

The ATHENA trial results were presented at the Society for Cardiovascular Angiography and Interventions (SCAI) 2016 Scientific Sessions in Orlando, Fla.

ADRCs are isolated from fat that is collected by means of liposuction. The processing procedure uses a Celution®System (Cytori Therapeutics, San Diego, CA) cell processing unit to separate the mature fat cells and red blood cells (and other unwanted material, i.e., connective tissue and so on) from the other cells. The processed material, or ADRC fraction is an admittedly mixed population of cells that includes some mesenchymal stem cells (a type of adult stem cell), endothelial progenitor cells, leukocytes (white blood cells), endothelial cells (which compose the inner lining of blood vessels), and vascular smooth muscle cells. Several studies in laboratory animals have shown that ADRCs can promote healing of scarred or injured tissue, but the precise exact mechanisms by which ADRCs do this is uncertain. Pre-clinical studies have shown that ADRCs can quell inflammation, stimulate new blood vessel formation, promote cell survival and prevent cell death, and secrete molecules that promote tissue repair and regeneration.

The key advantage of ADRCs come from the fact that fat is the richest source of adult stem and regenerative cells. For example, one gram of fat contains approximately 5,000 stem cells and these cells can be collected and processed in the same day.

The results of the ATHENA trial to data showed that the heart muscle of those who had received injections of their own ADRCs demonstrated symptomatic improvement and a trend towards lower rates of heart failure hospitalizations and angina (chest pain). However, there was no significant improvement in left ventricle ejection fraction (LVEF) or ventricular volumes.

“ADRCs consist of multiple cell types with multiple potential benefits,” said Timothy D. Henry, MD, MSCAI, director, division of cardiology at the Cedars-Sinai Heart Institute and the study’s lead investigator. “Based on the results seen with ADRCs in the PRECISE trial, we designed ATHENA to look at these cells as a possible treatment option for people with refractory chronic myocardial ischemia.”

This phase 2 program consisted of two prospective, randomized double-blind, placebo-controlled, parallel group trials that were called ATHENA and ATHENA II. The patients in this study had an average age of 65 years in both groups. 17 patients received injections of their own ADRCs into their heart muscle and 14 received the placebo. The ejection factions of these patients (the percentage of blood pumped out of the ventricles with each contraction) were between 20-45 percent (normal is around high 40s to low 50s). The ejection fraction or EF can be an early indicator of heart failure if it is 35 percent or below, and the baseline average EF score for both groups was 31.6 percent. The patients were also suffered from angina pectoris, a chest pain that occurs when the heart receives too little oxygen. All patients had blocked coronary arteries but were not candidates for revascularization therapies.

One year after receiving the therapy, the ADRC-treated patients registered improvement in their heart failure classification (57 percent) and angina classification (67 percent) relative to the placebo group (15 percent and 27 percent, respectively). Further, when evaluated with the Minnesota Living with Heart Failure questionnaire, the ADRC-treated patients showed distinct improvements over those who had received the placebo (-21.6 vs. -5.5, p=0.038), and displayed a trend toward fewer heart failure hospitalizations (centrally adjudicated [2/17, 11.7 percent vs. 2/14, 21.4 percent]). However, to emphasize again, there were no between group differences in LVEF or ventricular volume.

The ATHENA trial only examined a small patient population, but the results are potentially promising and consistent with what was seen with PRECISE and might provide the foundation for a large phase 3 trial.

The study, designed to enroll 90 patients, was terminated prematurely due to three neurological events that prolonged trial enrollment, but were not cell related.

The fact that patients feel better and do better with the ADRC treatment is encouraging, but without showing improved objective measures in heart physiology, such as increased ejection fraction, decreased end-diastolic volume and end-systolic volume, such a treatment will have a hard time finding enthusiastic endorsement among cardiologists.

Fat-Based Stem Cells in the PRECISE Trial Stabilizes Exercise Performance in Chronic Heart Disease Patients


Cytori Therapeutics has announced the publication of safety and efficacy data from a 36-month European clinical trial of Cytori Cell Therapy in patients with chronic ischemic heart failure. Final data from the Company’s PRECISE trial, a 27-patient, prospective, randomized, double-blind, placebo-controlled, feasibility trial (Phase I/IIA), demonstrated statistically significant differences in cardiac functional capacity between treated and placebo groups.

Their research will appear in the upcoming issue of the American Heart Journal. Cytori Cell Therapy is a mixed population of adipose derived regenerative cells (ADRCs™) extracted from a patient’s own adipose tissue using Cytori’s proprietary Celution® System.

“The PRECISE trial is the first-in-man trial involving the myocardial injection of ADRCs for heart disease,” said Dr. Emerson Perin , Co-Principal Investigator of the trial. “By demonstrating a strong safety profile and suggesting that the use of ADRCs may preserve functional capacity, the data indicates that this therapy may have meaningful impacts on the lives of these very sick patients.”

This particular publication was co-authored by trial investigators Drs. Emerson C. Perin at Texas Heart Institute, Francisco Fernández-Avilés at Hospital Universitario Gregorio Marañón and others. This clinical trial shows that the procedure was safe, feasible and showed indications of a favorable benefit to the patients who received it. The study demonstrated that fat harvest through liposuction could be performed safely in cardiac patients. Exercise capacity as reflected by maximum oxygen consumption (MVO2) during treadmill testing, a reflection of cardiac functional capacity, was sustained in the ADRC treated group but declined in the placebo group at 6 and 18 months. Statistically significant differences were observed between the two groups.

“These results supported the design of the ongoing U.S. Phase II ATHENA trial that is evaluating a similar patient population,” said Steven Kesten , M.D., Chief Medical Officer for Cytori. “We are encouraged by the sustained effects in functional endpoints, particularly MVO2, which is a relevant clinical endpoint in heart disease, and is an aid in directing treatment options, such as assist devices or heart transplant. We look forward to reporting the initial six-month results from the ATHENA trial.”

Additionally, other data trends in this study suggest that ADRC therapy may have a modest beneficial effect in stabilization of the heart scar tissue. To understand the meaning of this benefit, remember that ischemic heart disease might also be known as coronary artery disease (CAD), atherosclerotic heart disease, or coronary heart disease. Ischemic Heart Disease is the most common type of heart disease and cause of heart attacks. This disease is typically caused by plaque build up along the inner walls of the arteries of the heart, which leads to narrowing of the arteries and reduction of blood flow to the heart. After a heart attack, the region of the heart that was deprived of oxygen for a period time dies and the dead heart muscle tissue is replaced by scar tissue that contracts over time, but does not contract or conduct heartbeat impulses. In this study, the scar mass of the left ventricle remained consistent in ADRC-treated patients at six months compared to an increase in control patients. This suggests that ADRCs may prevent scar tissue from increasing. Other endpoints such as ventricular volumes and ejection fraction showed inconsistent findings.

In the PRECISE trial, all patients were treated with standard-of-care and subsequently underwent a liposuction procedure. Each patient’s adipose tissue was processed using Cytori’s proprietary Celution® System to prepare the cell therapy. Cells (n=21) or placebo (n=6) were injected into areas of the heart muscle that were severely damaged but still viable and reversible using the NOGA XP System.

Cytori is currently enrolling patients in the U.S. ATHENA and ATHENA II trials, both 45 patient prospective, randomized, double-blind, placebo-controlled trials investigating a lower and a higher dose, respectively, of Cytori Cell Therapy in a similar patient population as PRECISE.

The PRECISE study is a small study, but the fact that it was double-blinded and placebo controlled makes it an important study. The experimental group showed a clear stabilization of maximum oxygen consumption as opposed to the control group, whose exercise tolerance decreased during the course of the trial. This is potentially significant.  The ADRCs could be preventing the heart from enlarging as a result of working harder.

Questions, however, remain.  For example, is this a short-term effect or does it maintain its effect over the long-term period? To answer that, patient follow-up is necessary. Second, the other physiological parameters showed confusing outcomes (ejection fraction, end-diastolic volume, and so on).  If the ADRCs are truly helping the heart function better, then why don’t the physiological parameters used to measure heart function show some semblance of improvement?  The stabilization of the maximum oxygen consumption stabilization might not mean much in retrospect if it is short-term.

A larger trial like the ATHENA study will be more powerful. Hopefully these PRECISE patients will be followed and examined several years after the treatment to determine the duration of the ADR-provided benefits.

ATHENA Trial Tests Fat-Derived Stem Cells as a Treatment for Heart Failure


The FDA-approved ATHENA trial is the brainchild of stem cell researchers at the Texas Heart Institute at St. Luke’s Episcopal Hospital. The ATHENA trial is the first trial in the United States to examine the efficacy of adipose-derived regenerative cells or ADRCs as a treatment for a severe form of heart failure.

To harvest ADRCs, Texas Heart Institute researchers used a technique that was developed by Cytori Therapeutics, which is a biotechnology company that specializes in cell-based regenerative therapies. Previous clinical trials in Europe strongly suggest that such ADR-based therapies are quite safe and feasible. To date, physicians are the Texas Heart Institute have treated six patients as a part of the ATHENA trial.

athena_process_illustration_500x369.jpg

James Willerson, the president and medical director of the Texas Heart Institute, is the principal investigator in the ATHENA trial. Willerson said, “We have found that body fat tissue is a valuable source of regenerative stem cells that are relatively easy to access. We have high hopes for the therapeutic promise of this research and believe that it will lead quickly to larger trials.”

The subjects for the ATHENA trial are patients who suffer from chronic heart failure due to coronary heart disease. Coronary heart disease results from blockage of the coronary vessels and feed the heart muscle and limits the oxygen supply to the heart muscle, and consequently, the pumping activity of the heart muscle. Data from the American Heart Association reveals that there are about 5.1 million Americans who currently live with heart failure, and in many cases, the only viable treatment is a left ventricular assist device (LVAD) or a heart transplant. Unfortunately, there are only about 2,200 heart transplants a year due to a severe shortage of organs.

Coronary artery disease

Patients who are enrolled in the ATHENA trials are randomized and some will receive a placebo treatment and others will receive the experimental treatment. All patients will undergo liposuction in order to remove adipose or fat tissue. Processing of the fat tissue isolates the ADRCs, and the experimental patients will have these cells injected directly into their heart muscle, but the placebo patients will receive injections of culture medium or saline that contains no cells. ATHENA will measure several data endpoints that include objective measures of heart function, exercise capacity, and questionnaires that assess the symptoms and health-related quality-of-life.

The US trial will enroll a total of 45 patients at several centers around the country and these centers include the Texas Heart Institute, Minneapolis Heart Institute, Scripps Green Hospital in San Diego, CA, the University of Florida at Gainesville, and Cardiology P.C. in Birmingham. Patients are being enrolled.

Healthline has recently compiled the statistics on heart disease in an impressive and colorful manner at this link.