• DREAM-HF Stem Cell Trial Suggests Inflammatory Status May be Key to Effectiveness

    Therapy with mesenchymal precursor cells (MPC) reduces heart attacks, non-fatal strokes and cardiac death in patients with high-risk, heart failure with reduced ejection fraction (HFrEF) and high levels of inflammation, reveal data from the DREAM HF Trial.

    Findings from the study, which did not meet its primary endpoint of a reduction in non-fatal decompensated heart failure (HF) events but did reveal significant reductions in myocardial infarction (MI), stroke and death, were reported Sunday at the American Heart Association Scientific Sessions 2021.

    “It's interesting because it's hard to know the endpoints when you're dealing with a very new field,” said lead author Emerson C. Perin, MD, PhD, from the Texas Heart Institute, Houston. “This trial, given its size and follow-up, really helps us to understand a lot better what goes on.”

    He noted that the results suggest that traditional endpoints associated with recurrent HF hospitalization do not fully reveal the benefits or mechanisms of MPC stem cells on heart attack, stroke and death in patients with chronic HF.

    “This study addresses the inflammatory aspects of heart failure, which go mostly untreated, despite significant pharmaceutical and device therapy development,” he said, noting that cell therapy has the potential to change how HF is treated.

    “Our findings indicate stem cell therapy may be considered for use in addition to standard guideline therapies.”

    Stem cell therapy for HF?

    Perin noted that inflammation plays a significant role in the progression of HF over time, adding that in people with HFrEF, the heart muscle enlarges and weakens, resulting in a decrease in pumping ability and fluid buildup in the body’s tissues.

    MPCs are allogeneic STRO-1/STRO-3+ cells that are immunoselected from adult human bone marrow. Pre-clinical studies suggest that these stem cells have anti-inflammatory, immunomodulatory, and pro-angiogenic effects in models of ischemic and non-ischemic cardiomyopathy.

    Results from a phase II dosing study suggest that MPCs may reduce HF-associated events and adverse ventricular remodeling in patients with persistent HFrEF.

    In the new trial, researchers hypothesized that a single injection of these stem cells in addition to guideline-directed medical therapy for HF would affect the number of times participants were hospitalized for HF events and reduce heart attacks, strokes or death.

    Trial data

    The DREAM (Randomized Trial of Targeted Transendocardial Delivery of Mesenchymal Precursor Cells in High-Risk Chronic Heart Failure Patients with Reduced Ejection Fraction) trial is the largest study of stem cell therapy in people with HF to date.

    The multicenter, randomized, sham-controlled, double-blind trial, enrolled 537 participants (average age 63, 20% female) with HFrEF. HF was defined using the New York Heart Association (NYHA) functional classification system, which puts patients into one of four categories based on how much they are limited during physical activity.

    Participants in the trial were randomly divided into two groups, explained Perin, noting that 261 adults received an injection of 150 million MPCs directly into the heart using a catheter, while the remaining 276 adults received a sham procedure.

    “Cells were delivered through 15-20 injections directly into the myocardium via a catheter using a sophisticated real-time 3D mapping system,” said Perin, noting that patients were then followed for an average of 30 months post-procedure.

    While the investigators did not see a decrease in their primary endpoint of hospitalizations, they did report several significant results.

    “We saw a significant reduction, of 65%, in all of the treated population with MPCs in incidence of MI or nonfatal stroke,” said Perin.

    Furthermore, he revealed that cardiac death was reduced by 57% in NYHA class II patients, while there was no effect in the general population or in class III patients.

    Is inflammatory status the key?

    The researcher noted that the “most important” finding from the trial comes when inflammatory status is taken into account.

    “We looked at plasma baseline levels of C-reactive protein [CRP] and classified the patients as either inflamed or non-inflamed,” said Perin, noting a threshold of CRP levels of 2 mg/L to define high levels of inflammation.

    He revealed that whose people with high levels of inflammation were 79% less likely to have a non-fatal heart attack or stroke after being treated with stem cells, while treatment reduced cardiac death by 80% in people with high levels of inflammation and less severe, class II HF.

    “If you look at the patients that didn't have the inflammation, there is no benefit at all,” said Perin.

    “So, with that magnitude of benefit, we know where the benefits of the cells are. We know that if patients aren't inflamed then this therapy really isn't going to help them.”

    He said that while the primary endpoint, which was related to traditional HF symptoms, was not improved by MPCs, the trial has hinted at mechanisms of action for MPCs.

    “For the first time, the known anti-inflammatory mechanism of action of these cells may be linked to a cause-and-effect benefit in heart failure. The stem cells acted locally in the heart, and they also helped in blood vessels throughout the body,” said Perin, noting that this systemic effect on the large vessels in the brain and heart is associated with a decrease in heart attacks and stroke.

    He added that further research is needed to better understand how these stem cells may affect the course of progression of heart failure and how these therapies may be directed to the patient groups that could see the most benefits.

    “This is a really interesting example of personalized medicine,” he said.

    “We're identifying the patients that can benefit through the CRP, and then we are using a very precise way of delivering these cells in each individual patient to exactly where they need to be placed ... which we can identify with the mapping system.”

    The study was funded by Mesoblast Inc., manufacturer of the MPCs used in the study.

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