Evaluation of the clinical relevance and limitations of current pre-clinical models of peripheral artery disease

Peripheral arterial disease (PAD) usually results from atherosclerosis and associated thrombosis and limits blood supply to the lower limbs. Common presenting symptoms include intermittent claudication (IC), rest pain and tissue loss. When limb viability is threatened, known as critical limb ischaemia (CLI), surgical and endovascular interventions are frequently undertaken; however, these are not always successful and ultimately major amputation may be required. There is significant interest in developing new therapeutic approaches to manage PAD which can be applied to patients unlikely to benefit from interventional approaches. Many of the therapeutic agents successful in inducing angiogenesis and arteriogenesis in pre-clinical animal models of PAD have failed to have efficacy in human randomized control trials. One possible reason for this inability to translate findings to patients could be the type of pre-clinical animal models used. In the present review, we describe currently available pre-clinical models of PAD and discuss the advantages and disadvantages of the available models. A detailed assessment of the currently available pre-clinical animal models shows major limitations such as variability in the surgical procedure used to induce limb ischaemia, variability in the strains of rodents used, lack of risk factors incorporated into the model and lack of standardized functional outcomes. The most commonly used outcome assessments in studies within pre-clinical models differ from those employed in clinical trials within PAD patients. Most current pre-clinical models are designed to produce acute ischaemia which leads to muscle necrosis and inflammation. Patients, however, most commonly present with chronic ischaemia suggesting that more representative models are needed to evaluate therapeutic modalities that can be potentially translated to clinical practice.