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Shyam Bhakta, MD, MBA, FACC, FAHA, FSCAI
Cardiovascular Interdisciplinary Program and Working Group, National Center for Regenerative
Medicine, Case Western Reserve University
Cleveland, Ohio  USA

Cardiovascular disease is the leading cause of death and disability in the United States, the Western hemisphere, and, increasingly, in developing nations. Congestive heart failure that results from ischemic cardiomyopathy – as a result of prior heart attack or coronary artery disease – as well as nonischemic cardiomyopathy – as a result of prior viral myocarditis, for instance – is the leading cause of hospitalization in the United States. Despite advances in diagnosis, corrective procedures, and medical therapy, mortality in patients with congestive heart failure is as high as 50 percent at five years.

In addition to ischemic heart disease and other sources of myocardial injury, inflammation is implicated in the pathogenesis and progression of congestive heart failure. Ischemic cardiomyopathy, which is the most common cause of congestive heart failure in developed nations, is also caused by immunological and inflammatory processes.

Mesenchymal precursor cells (MPCs) are allogeneic-derived STRO-1/STRO-3-positive cells derived from human bone marrow mononuclear cells from healthy donors. MPCs have immunomodulatory properties and express cell surface markers for proinflammatory cytokines produced by activated macrophages and T-cells. Preclinical studies have demonstrated that MPCs and mesenchymal stem cells (MSCs) reduce macrophage-dependent inflammation and also release angiogenic factors in regions of ischemia to improve microvascular function. Increases in endothelial nitric oxide synthase activity leads to increased nitric oxide production, improvement in endothelial function, and improved myocardial perfusion and function.

The Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Heart Failure (DREAM-HF; clinicaltrials.gov identifier NCT02032004) trial was published recently (1) and studied the safety and efficacy of MPCs in patients with systolic heart failure. The study enrolled 565 patients with systolic heart failure – defined as a left ventricle ejection fraction less than 40 percent by echocardiography or 35 percent by multigated acquisition (MUGA) scan – to receive either placebo/standard therapy or a total of 15 – 20 injections of 0.2-mL injections containing eight – 10 million MPCs for a total cell dose of 150 million cells.

Allogenic bone marrow MPCs were derived from three healthy adult donors and were obtained by using monoclonal antibody with specificity against STRO-3 and magnetic bead-based cell separation technology. Selected cells were culture-expanded and stored in liquid nitrogen until thawed for use. A pre-specified subgroup analysis was performed based on plasma levels of high-sensitivity C-reactive protein (hsCRP) exceeding 2 mg/L.

As above, a total of 565 patients were randomized – 282 to placebo/standard therapy and 283 to MPCs per protocol. Approximately equal numbers of patients in each study arm had New York Heart Association (NYHA) class 2 or 3 heart failure as well as ischemic versus nonischemic cardiomyopathies. While the primary endpoint of worsening heart failure was no different in the two treatment arms, the study did find a statistically significant increase in left ventricle ejection fraction of three percent in the cell therapy arm in patients whose baseline hsCRP exceeded 2 mg/L. In addition, the study found a 58 percent reduction in heart attack or stroke in patients receiving cell therapy, a difference driven largely based on positive effects in patients whose hsCRP exceeded 2 mg/L compared to those whose hsCRP levels did not.

The DREAM-HF trial is the largest cell therapy clinical trial in systolic heart failure. The MPC-based therapy appeared to derive its benefit by being activated by local cytokines in affected myocardium, leading to improvements in the inflammatory environment. MPCs are STRO-1/STRO-3+ and demonstrate greater immunomodulatory activity than MSCs, which are STRO-1-negative. MPCs are believed to bind proinflammatory cytokines in myocardium in systolic heart failure, resulting in release of anti-inflammatory factors that contribute to neovascularization. Preclinical studies demonstrated the ability of MPCs to improve endothelial function as well as stimulating angiogenesis and vasculogenesis in myocardium in systolic heart failure.

In addition, MPCs convert M1 proinflammatory macrophages to M2 anti-inflammatory macrophages in atherosclerotic endothelium, potentially preventing thrombus formation and plaque rupture, which is the main driver of sudden cardiac events, such as heart attack and cardiac arrest. Angiogenesis protects ischemic myocardium from apoptosis and subsequent fibrosis.

Myocardial injury is accompanied by inflammation. M1 macrophages attracted to the site of injury release interleukin (IL)-6, which stimulates hepatic production of CRP. MPCs convert M1 macrophages to M2 macrophages, which produce IL-10, which stimulates cardiomyocyte survival; platelet-derived growth factor (PDGF), which affects smooth muscle cell function; and fibroblast growth factor (FGF)-2, which, in conjuction with stromal cell derived factor (SDF)-1, vascular endothelial growth factor (VEGF), and angiopoetin-1 (ANG-1), stimulates neovascularization.

As of November 2022, there are 125 completed and 142 ongoing clinical trials using MSCs, which have been shown in preclinical studies to improve cardiac function following transplantation without developing into cardiomyocytes, suggesting release of local mediators that improve inflammation and immune responses as well as vasculogenesis, While the DREAM-HF study utilized catheter-based endomyocardial cell delivery, there is great interest in utilizing an intravenous/parenteral approach due to its safety, low cost, and ability to administer serial cell doses to eligible patients. While many MSCs given intravenously become trapped in the lungs and the reticuloendothelial system, i.e., the spleen and liver, uptake of their debris following apoptosis by monocytes is felt to lead to decreased inflammatory signals and increased anti-inflammatory mechanisms such as regulatory T-cells and M2 macrophages.

In summary, the DREAM-HF trial, while its primary endpoint was negative, was still a noteworthy trial in that it demonstrated benefit of MPC therapy in patients with chronic heart failure who demonstrated evidence of increased inflammation, as measured by levels of hsCRP. This trial should lead to continued interest in the development of cell- and gene therapy-based treatments to congestive heart failure based on anti-inflammatory and immunomodulatory properties.

References

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