Background

Critical limb ischemia represents a therapeutic dead end for many patients. The 2023 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Disease emphasize the importance of revascularization (surgical or endovascular) as the primary treatment strategy for CLI. However, these guidelines also acknowledge that a significant proportion of patients are not suitable candidates for these procedures, or they experience recurrent ischemia despite successful revascularization. This leaves a large unmet need for alternative or adjunctive therapies.

The rationale behind using CD34+ cells stems from their ability to promote angiogenesis, the formation of new blood vessels, in ischemic tissues. Hyperbaric oxygen therapy, on the other hand, increases the amount of oxygen dissolved in the blood, potentially enhancing tissue oxygenation and promoting wound healing. The hypothesis is that HBOT can 'prime' the ischemic environment, making it more receptive to the angiogenic effects of CD34+ cells. But does this combination actually work, and is the evidence strong enough to justify its use?

Methodology

The study involved patients with PAOD who were treated with CD34+ cells and HBOT. The researchers isolated endothelial progenitor cells (EPCs) from these patients and assessed their ability to promote angiogenesis in a nude mouse model of critical limb ischemia. Specifically, they induced hindlimb ischemia in these mice and then transplanted EPCs derived from the treated PAOD patients. The primary outcome was limb salvage, assessed by measuring blood flow recovery and tissue necrosis.

While the use of a nude mouse model allows for controlled experimentation without the confounding effects of an immune response, it's a far cry from the complex reality of human peripheral arterial disease. The study's reliance on EPCs as a surrogate marker for clinical efficacy also raises questions. Are these in vitro findings truly predictive of improved outcomes in patients with CLI?

Results

The results showed that EPCs derived from PAOD patients treated with CD34+ cells and HBOT significantly improved limb salvage in the nude mouse model. Specifically, they observed enhanced blood flow recovery and reduced tissue necrosis compared to control groups. The researchers also demonstrated that these "rejuvenated" EPCs exhibited increased angiogenic potential in vitro.

It's important to note that these are preclinical data. While promising, they do not directly translate to clinical benefit in humans. The observed improvements in blood flow and tissue preservation in mice need to be replicated in well-designed clinical trials before this combined therapy can be considered a viable treatment option for CLI patients.

Clinical Guidelines

As noted above, current guidelines such as the 2023 ESC PAD guidelines place endovascular or open surgical revascularization at the forefront of CLI management. Cell-based therapies are not mentioned as a standard of care. This study does not provide sufficient evidence to alter these recommendations. The American Heart Association (AHA) also does not endorse cell therapies for PAD outside of clinical trial settings.

Until robust clinical trial data demonstrate a clear benefit with acceptable safety, the use of HBOT and CD34+ cell therapy in CLI should be restricted to investigational protocols. Premature adoption could expose patients to unnecessary risks and costs.

Limitations

Several limitations warrant careful consideration. First, the study's reliance on a nude mouse model limits its translational relevance. The pathophysiology of CLI in humans is far more complex than what can be replicated in mice. Second, the sample size of PAOD patients was not reported in this summary, but it is unlikely that this was a large cohort, so there may be a bias in the selection of patients. Third, the absence of a control group receiving either CD34+ cells or HBOT alone makes it difficult to determine the independent contribution of each therapy. This is a major flaw.

Furthermore, long-term follow-up data are lacking. The study only assessed limb salvage at a relatively short time point. The durability of the observed benefits remains unknown. What happens after six months? One year? Are repeat treatments necessary? These questions need to be addressed in future studies.

Clinical Implications