First-in-Man Study Demonstrates Safety, Feasibility of Adipose-Derived Cell Therapy for Heart Failure

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In a ‘no options’ patient with chronic ischemic heart disease, transendocardial injection of autologous adipose-derived regenerative cells appears safe and yields signals of efficacy, including preservation of functional capacity over 18 months. The findings from a first-in-man study were published online April 7, 2014, ahead of print in the American Heart Journal.

Data from the PRECISE trial were initially presented at the Transcatheter Cardiovascular Therapeutics scientific symposium in San Francisco, CA, in November 2011.

Francisco Fernández-Avilés, MD, PhD, of Hospital General Universitario Gregorio Marañón (Madrid, Spain), and colleagues randomized, in a 3:1 fashion, 27 patients with chronic ischemic cardiomyopathy and no option of revascularization to receive transendocardial injection of autologous regenerative cells (mean 42 x 106 cells in a 3 mL volume; n = 21) or placebo (n = 6) at 4 European sites.

Fat-Cell Harvesting Safe

All patients first underwent harvesting of abdominal adipose tissue. The regenerative cells were isolated using the Celution System (Cytori Therapeutics; San Diego, CA) and then delivered in 15 injections guided by the catheter-based NOGA XP navigation system (Biologics Delivery Systems; Diamond Bar, CA). Control patients received the same pattern of injections and solution but without cell therapy.

Fat harvesting, performed under local anesthesia, was well tolerated with no procedure-related complications. NOGA mapping and transendocardial injection were not associated with sustained arrhythmias.

In the cell-therapy group, 1 patient suffered mild pericardial effusion after injection, another had a periprocedural NSTEMI, and a third experienced TIAs at 6 and 11 months after treatment. Of 5 deaths, 3 occurred in the cell-therapy group, and 1 of those was cardiac-related. No malignant arrhythmias were associated with the procedures or were seen at follow-up. Moreover, there were no significant changes from baseline in laboratory parameters.

Modest improvements in New York Heart Association (NYHA) and Canadian Cardiovascular Society class were seen in both arms, although there were no significant changes in LVEF or LV volume within each group over time or between groups. LV total mass, as measured by cardiac MRI, increased from baseline to 6 months in the cell-therapy group (from 128.1 ± 26.0 g to 149.5 ± 32.4 g; P < 0.001), as did global wall motion score index (from 2.1 ± 0.6 to 1.7 ± 0.9; P = 0.04). Both of these metrics remained unchanged in the control group.

In terms of exercise tolerance, metabolic equivalent values were preserved over 18 months in the treatment group, while they decreased in the control group (P = 0.001). Over the same period, maximal oxygen consumption (MVO2) was maintained in the cell-therapy group but declined in the control group (from 19.0 ± 8.2 mL/kg/min to 14.8 ± 16.9 mL/kg/min; P = 0.001).

In addition, the summed stress-rest difference score at 6 months was lower in the treatment group (P = 0.02) but remained unchanged in the control group, suggesting less stress-induced ischemia in cell-therapy patients. This difference was sustained over 18 months. Furthermore, visual summed wall motion at 6 months increased in cell-treated patients (from 25.2 ± 11.5 to 27.6 ± 10.8; P = 0.03) but not in the control group.

Advantages Over Bone Marrow Cells

In a telephone interview with TCTMD, co-principal investigator Emerson C. Perin, MD, PhD, of the Texas Heart Institute (Houston, TX), explained the rationale behind the researchers’ choice of therapeutic cells. “We have studied bone marrow in heart failure, and it is a relatively weak therapy. Now we are looking for stronger therapies, and this may be one of them,” he said.

Not only are adipose-derived cells relatively easy to obtain and ready for injection within hours of harvesting, but their quality and composition appear to be more favorable than those derived from bone marrow, Dr. Perin contended. Key mesenchymal cells are far more abundant in the stromal vascular fraction isolated from adipose tissue, which is also rich in mesenchymal-like pericytes and endothelial progenitor cells, he said, adding that pro-healing macrophages predominate over the pro-inflammatory type.

Adipose-derived regenerative cell therapy is thought to work primarily through a paracrine mechanism “on multiple fronts,” Dr. Perin said, releasing pro-angiogenic and anti-apoptotic factors, for example, rather than by directly regenerating heart muscle. In addition, noncardiac research shows that the therapy may modify scars in such a way that the tissue of infarcted heart muscle might become more compliant, he reported.

Furthermore, use of regenerative cells from adipose tissue avoids an important drawback of autologous bone marrow since fat cells are much less affected by variables such as age and comorbidities, Dr. Perin noted, adding that the observation requires confirmation.

Another important component of the current strategy is the 3-D mapping of the left ventricle with the NOGA navigation system, Dr. Perin said. This enables specific targeting of tissue that is ischemic yet still viable.

Safe with a Hint of Efficacy

Since all patients were very sick and the cell strategy was brand new, the main goal of the PRECISE trial was to show that the procedure was well tolerated and safe, Dr. Perin emphasized.

But the MVO2 trend in particular is an important efficacy signal, he asserted. Over follow-up, placebo patients’ peak oxygen consumption declined to a threshold that qualified them for heart transplant, while those treated with cell therapy remained stable. Furthermore, MVO2 is a more important measure of functional capacity than LVEF and is a strong predictor of mortality, Dr. Perin noted.

Next up for adipose-derived cell therapy in chronic ischemic heart disease is ATHENA, a randomized controlled trial currently enrolling 45 subjects at 8 US centers, he reported.

Study Details

Patients had NYHA class II-III symptoms, LVEF ≤ 45% as determined by 2-D transthoracic echocardiography, and evidence of a stress-induced reversible perfusion defect on SPECT within 1 month of enrollment.

 


Source:
Perin EC, Sanz-Ruiz R, Sánchez PL, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE trial. Am Heart J. 2014;Epub ahead of print.

 

 

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Disclosures
  • The PRECISE trial was supported by Cytori Therapeutics.
  • Dr. Fernández-Avilés reports no relevant conflicts of interest.
  • Dr. Perin reports receiving consulting fees from Amorcyte, Cytori Therapeutics, St. Jude Medical, and Teva; his spouse is employed by Cytori.

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